Novel compounds

ABSTRACT

A compound of formula (I): 
     
       
         
         
             
             
         
       
         
         or a salt thereof; 
         which is an inhibitor of spleen tyrosine kinase (SYK) and therefore potentially of use in treating diseases resulting from inappropriate activation of mast cells, macrophages, and B-cells and related inflammatory responses and tissue damage, for instance inflammatory diseases and/or allergic conditions, in cancer therapy, specifically heme malignancies, and autoimmune conditions.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a Continuation of U.S. application Ser. No.13/414,873, filed on Mar. 8, 2012, which claims the benefit of GBApplication No. 1104153.0 filed on Mar. 11, 2011 in the United Kingdom.

FIELD OF THE INVENTION

The present invention relates to novel chemical compounds which haveactivity against spleen tyrosine kinase (Syk), processes for theirpreparation, pharmaceutically acceptable formulations containing themand their use in therapy.

BACKGROUND

Syk is a non-receptor tyrosine kinase that is involved in couplingactivated immunoreceptors to signal downstream events that mediatediverse cellular responses, including proliferation, differentiation,and phagocytosis. Syk is widely expressed in hematopoietic cells. Sykinhibitors have potential anti-inflammatory and immunomodulatingactivities. They inhibit Syk-mediated IgG Fc epsilon and gamma receptorand BCR receptor signalling, resulting in inhibition of the activationof mast cells, macrophages, and B-cells and related inflammatoryresponses and tissue damage. Mast cells play a major role in type Ihypersensitivity reactions and have been implicated in urticaria,bronchial asthma, anaphylaxis and other allergic conditions.Accordingly, Syk inhibitors have attracted interest in a number oftherapeutic areas, including the treatment of rheumatoid arthritis,B-cell lymphoma, asthma, rhinitis and cutaneous disorders such as acuteand chronic urticaria, mastocytosis, cutaneous lupus, atopic dermatitis,autoimmune bullous conditions including pemphigus and pemphigoid andother mast cell mediated diseases of the skin.

Acute and chronic urticaria are common skin diseases thought to affectaround 25% of the total population within the USA. Although urticariacan be triggered by allergic reactions many cases have an unclearetiology. Chronic urticaria is defined as when wide spread wheals arepresent for greater than 6 weeks. There are many pathologicalsimilarities in chronic urticaria patients, in terms of extent of whealsin the skin, with allergen-induced mast and basophil cell degranulationreactions via IgE activation. Around 40% of chronic urticaria patientscontain serum IgG auto-antibodies targeting IgE or the IgE receptor (FcEpsilon Receptor) and these are thought to drive the histamine and othermediator release via mast and basophil degranulation. Syk inhibitorswould inhibit the signalling response post IgE mediated Fc Epsilonactivation and inhibit the mediator release known to be involved inchronic pruritis in multiple diseases.

Cutaneous mastocytosis is defined as an excessive accumulation of mastcells in the skin normally seen in both the paediatric and adultpopulation. It is a rare disease thought to be due to a dysregulation inthe proliferative capacity of the mast cells. The excessive productionof mast cells in the skin leads to an increased release of cytokines andhistamines which lead to itching, skin lesions, and in some cases wherethere is a systemic involvement, anaphylactic shock or low bloodpressure.

Cutaneous lupus is a condition of the skin found in some patients with adiscoid form of lupus erythematosus. The disorder is characterised by ared raised rash on the face or scalp and other areas of the body andmast cells and antibody deposition are known to be involved in thelesions.

A Syk inhibitor applied topically would decrease the production ofcytokines, histamines and other mediators potentially leading to reduceditching and inflammatory infiltration in the skin.

Atopic dermatitis is a very common and sometimes long lastinginflammatory skin disorder characterised by redness and pruritis. Thedisease often occurs with other allergic conditions such as hay fever orasthma, is found predominantly in young children and is exacerbated bycontact with allergens. Mast cell involvement is understood to lead tothe characteristic itching and excessive scratching which can lead to anincrease in bacterial infections in the skin. Topical application of aSyk inhibitor could reduce these symptoms.

Autoimmune bullous conditions including pemphigus and pemphigoid areacute and chronic skin diseases involving the formation of blisters.Bullous pemphigoid (BP) is a chronic, autoimmune, subepidermal,blistering skin disorder (unlike pemphigus where the blistering isintraepidermal). These rare diseases generally affect people over theage of 70. Autoantibodies are generated against the basement membranelayer of the skin leading to activation of complement and otherinflammatory mediators. The inflammatory process initiates a release ofenzymes which degrade proteins in the hemidesmosomal layers eventuallyleading to blisters as the layers of the skin fall apart. An urticarialrash and pruritis generally occur prior to onset of the blisters, soinhibition of mast cell degranulation and cytokine production post IgGantibody activation in macrophages with a Syk inhibitor could bebeneficial in these diseases.

Rheumatoid arthritis (RA) is an autoimmune disease affectingapproximately 1% of the population. It is characterised by inflammationof articular joints leading to debilitating destruction of bone andcartilage. Recent clinical studies with rituximab, which causes areversible B cell depletion, (J. C. W. Edwards et al. 2004, New Eng. J.Med. 350: 2572-2581), have shown that targeting B cell function is anappropriate therapeutic strategy in autoimmune diseases such as RA.Clinical benefit correlates with a reduction in auto-reactive antibodies(or rheumatoid Ffactor) and these studies suggest that B cell functionand indeed auto-antibody production are central to the ongoing pathologyin the disease.

Studies using cells from mice deficient in Syk have demonstrated anon-redundant role of this kinase in B cell function. The deficiency inSyk is characterised by a block in B cell development (M. Turner et al1995 Nature 379: 298-302 and Cheng et al 1995, Nature 378: 303-306).These studies, along with studies on mature B cells deficient in Syk(Kurasaki et al 2000, Immunol. Rev. 176:19-29), demonstrate that Syk isrequired for the differentiation and activation of B cells. Hence,inhibition of Syk in RA patients is likely to block B cell function andhence reduce rheumatoid factor production. In addition to the role ofSyk in B cell function, of relevance to the treatment of RA, is therequirement for Syk activity in Fc receptor (FcR) signalling. FcRactivation by immune complexes in RA has been suggested to contribute tothe release of multiple pro-inflammatory mediators.

The contribution of Syk dependent processes to the pathology of RA hasbeen reviewed by Wong et al (2004, ibid).

The results of a 12 week proof of concept clinical trial for the Sykinhibitor R788 (fostamatinib disodium, Rigel) have been published:Treatment of rheumatoid arthritis with a Syk inhibitor: A twelve-week,randomized, placebo-controlled trial, Arthritis & Rheumatis, 58(11),2008, 3309-3318.

Syk inhibitors may also be useful in cancer therapy, specifically hememalignancies, particularly Non-Hodgkin's Lymphomas including follicular(FL), mantle cell, Burkitt and diffuse large B cell (DLBCL) lymphomas.

Studies have shown that Syk is dysregulated by overexpression and/orconstitutively activation in a variety of primary B-lymphoma tumours andalso in B-lymphoma cell lines. Syk, through the PI3K/AKT pathway, thePLD pathway and AKT independent signalling, activates mTOR (mammaliantarget of rapamycin) which in turn increases B-cell survival andproliferation. Inhibition of Syk in vitro, results in decreased mTORactivation and a reduction of clonicity in FL cells. Inhibition of Sykwith curcumin in a murine model of B lymphoma (BKS-2) gave a significantreduction of tumour burden as measured by the total splenocyte number.(Leseux L. et al. Blood 15 Dec. 2006, Vol 108, No 13 pp 4156-4162 andGururajan M. et al. Journal of Immunology, 2007, 178 pp 111-121).

Results of a Phase 2 clinical trial of R788 (fostamatinib disodium) inpatients with relapsed or refractory B-Cell non-Hodgkin's lymphoma (NHL)show that the compound is well-tolerated by these patients, as well as atherapeutic benefit in patients suffering from diffuse large B-Celllymphoma (DLBCL) and chronic lymphocytic leukemia/small lymphocyticlymphoma (CLUSLL). Despite the fact that the patients enrolled in thistrial had advanced disease and had failed treatment with marketedtherapies, a significant number of them were particularly responsive toSyk inhibition with R788 (Chen et al. Blood 2008 Vol 111 pp 2230-2237,www.Rigel.com)

Syk inhibitors may also be useful in the treatment of asthma andallergic rhinitis as they are important in transducing the downstreamcellular signals associated with cross-linking FcεR1 and or FcγR1receptors, and Syk is positioned early in the signalling cascade. Inmast cells, for example, the early sequence of FcεR1 signallingfollowing allergen cross-linking of receptor-IgE complexes involvesfirst Lyn (a Src family tyrosine kinase) and then Syk.

Allergic rhinitis and asthma are diseases associated withhypersensitivity reactions and inflammatory events involving a multitudeof cell types including mast cells, eosinophils, T cells and dendriticcells. Following exposure to allergen, high affinity immunoglobulinreceptors for IgE (FcεRI) and IgG (FcγRI) become cross-linked andactivate downstream processes in mast cells and other cell types leadingto the release of pro-inflammatory mediators and airway spasmogens. Inthe mast cell, for example, IgE receptor cross-linking by allergen leadsto release of mediators including histamine from pre-formed granules, aswell as the synthesis and release of newly synthesised lipid mediatorsincluding prostaglandins and leukotrienes.

The Syk inhibitor R112 (Rigel), dosed intranasally in a phase I/II studyfor the treatment of allergic rhinitis, was shown to give astatistically significant decrease in PGD₂, a key immune mediator thatis highly correlated with improvements in allergic rhinorrhea, as wellas being safe across a range of indicators, thus providing the firstevidence for the clinical safety and efficacy of a topical Syk inhibitor(see Meltzer, Eli O.; Berkowitz, Robert B.; Grossbard, Elliott B. Anintranasal Syk inhibitor (R112) improves the symptoms of seasonalallergic rhinitis in a park environment. Journal of Allergy and ClinicalImmunology (2005), 115(4), 791-796). In a further phase II clinicaltrial, for allergic rhinitis, R112 was however shown as having a lack ofefficacy versus placebo (Clinical Trials.gov Identifier NCT0015089).

WO 03/057695 (Boehringer Ingelheim Pharmaceuticals, Inc) describes 1,6Naphthyridines that have Syk inhibitory activity. These are furtherdescribed in “Discovery and SAR of Novel [1,6] Naphthyridines as PotentInhibitors of Spleen Tyrosine Kinase (SYK) (Bioorganic & MedicinalChemistry Letters 13 (2003) 1415-1418). This has been followed with twomore recent patent applications, WO 2010/015518 and WO 2010/015529(Boehringer Ingelheim Pharmaceuticals, Inc), describing4-dimethylamino-phenyl-substituted naphthyridines and substitutednaphthyridines, respectively.

WO 04/035604 discloses the structural co-ordinates of the human Sykprotein.

There remains however the need to identify further compounds which areinhibitors of Syk.

BRIEF SUMMARY OF THE INVENTION

The present invention relates to novel chemical compounds which haveactivity against spleen tyrosine kinase (Syk), processes for theirpreparation, pharmaceutically acceptable formulations containing themand their use in therapy.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the XRPD diffraction pattern for FORM 1.

FIG. 2 shows the FT-Raman Spectrum for FORM 1.

FIG. 3 shows the DSC thermogram of FORM 1.

FIG. 4 shows the XRPD diffraction pattern for FORM 2.

FIG. 5 shows the FT-Ramen Spectrum for FORM 2.

FIG. 6 shows DSC thermogram of FORM 2.

DETAILED DESCRIPTION OF THE INVENTION

Thus, in one embodiment, the present invention provides a compound offormula (I):

wherein:

X is CR₁ or N;

Y is CH, C or N;

R₁ is hydrogen, C₁₋₆alkoxy or C₁₋₆alkyl;

R₂ is hydrogen, C₁₋₆alkoxy, halo, —C(O)C₁₋₆alkyl, CN, Halo-C₁₋₆alkyl orC(O)NR₄R₅;

R₃ is hydrogen or C₁₋₆alkoxy;

R₄ is hydrogen or C₁₋₆alkyl:

R₅ is hydrogen or C₁₋₆alkyl and

m and n are integers each independently selected from 1 and 2; or a saltthereof.

In one embodiment, the invention provides a compound of formula (Ia);

wherein:

X is CR₁ or N;

Y is CH, C or N;

R₁ is hydrogen, C₁₋₆alkoxy or C₁₋₆alkyl;

R₂ is hydrogen, C₁₋₆alkoxy, halo or —C(O)C₁₋₆alkyl; and

m and n are integers each independently selected from 1 and 2; or a saltthereof.

In one embodiment X is CR₁ or N. In another embodiment X is CR₁.

In one embodiment Y is CH, C or N. In another embodiment Y is CH. Inanother embodiment Y is C. In a further embodiment Y is N.

In one embodiment R₁ is hydrogen, C₁₋₆alkoxy or C₁₋₆alkyl. In anotherembodiment R₁ is methyl, methoxy or hydrogen.

In one embodiment R₂ is hydrogen, C₁₋₆alkoxy, halo, —C(O)C₁₋₆alkyl, CN,Halo-C₁₋₆₋ alkyl or C(O)NR₄R₅. In one embodiment R₂ is hydrogen,C₁₋₆alkoxy, halo or —C(O)C₁₋₆alkyl. In another embodiment R₂ ishydrogen, methoxy, fluoro, —C(O)CH₃ or trifluoromethyl. In anotherembodiment R₂ is hydrogen, methoxy, fluoro or —C(O)CH₃. In a furtherembodiment R₂ is hydrogen, methoxy or —C(O)CH₃.

In one embodiment R₃ is hydrogen or C₁₋₆alkoxy. In one embodiment R₃ ishydrogen, or methoxy.

In one embodiment R₄ is hydrogen or C₁₋₆alkyl. In another embodiment R₄is hydrogen or C₁₋₄alkyl. In a further embodiment R₄ is hydrogen ormethyl.

In one embodiment R₅ is hydrogen or C₁₋₆alkyl. In another embodiment R₅is hydrogen or C₁₋₄alkyl. In a further embodiment R₅ is hydrogen ormethyl.

In one embodiment m and n are integers each independently selected from1 and 2. In another embodiment m is 2 and n is 1 or 2. In anotherembodiment n is 1 and m is 1 or 2. In a further embodiment m and n areboth 2.

In one embodiment X is CR₁, and R₁ is methyl. In another embodiment, Xis CR₁, R₁ is methyl and Y is C. In a further embodiment, X is CR₁, R₁is methyl, Y is C and R₂₋is methoxy. In a yet further embodiment, X isCR₁, R₁ is methyl, Y is C, R₂ is methoxy and R₃ is hydrogen. In a stillfurther embodiment, X is CR₁, R₁ is methyl, Y is C, R₂ is methoxy, R₃ ishydrogen, m is 2 and n is 2.

In one embodiment, the compound of formula (I) is selected from:

7-(3-{[(4-methyl-2-pyridinyl)methyl]oxy}-2-pyridinyl)-2,3,4,5-tetrahydro-1H-3-benzazepine;

7-(2-(methyloxy)-6-{[(4-methyl-2-pyridinyl)methyl]oxy}phenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine;

7-(4-(methyloxy)-2-{[(4-methyl-2-pyridinyl)methyl]oxy}phenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine;

1-[4-{[(4-methyl-2-pyridinyl)methyl]oxy}-3-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)phenyl]ethanone;

7-(6-methyl-3-{[(4-methyl-2-pyridinyl)methyl]oxy}-2-pyridinyl)-2,3,4,5-tetrahydro-1H-3-benzazepine;

1-[4-[(2-pyrazinylmethyl)oxy]-3-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)phenyl]ethanone;

7-(5-fluoro-2-{[(4-methyl-2-pyridinyl)methyl]oxy}phenyl)-1,2,3,4-tetrahydroisoquinoline;

7-(5-methyl-2-{[(4-methyl-2-pyridinyl)methyl]oxy}phenyl)-1,2,3,4-tetrahydroisoquinoline;

7-(2-(methyloxy)-6-{[(4-methyl-2-pyridinyl)methyl]oxy}phenyl)-1,2,3,4-tetrahydroisoquinoline;

7-(5-(ethyloxy)-2-{[(4-methyl-2-pyridinyl)methyl]oxy}phenyl)-1,2,3,4-tetrahydroisoquinoline;

7-(4-(methyloxy)-2-{[(4-methyl-2-pyridinyl)methyl]oxy}phenyl)-1,2,3,4-tetrahydroisoquinoline;

4-{[(4-methyl-2-pyridinyl)methyl]oxy}-3-(1,2,3,4-tetrahydro-7-isoquinolinyl)benzonitrile;

7-[2-{[(4-methyl-2-pyridinyl)methyl]oxy}-5-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydroisoquinoline;

7-(5-(methyloxy)-2-{[(4-methyl-2-pyridinyl)methyl]oxy}phenyl)-1,2,3,4-tetrahydroisoquinoline;

7-(5-(1,1-dimethylethyl)-2-{[(4-methyl-2-pyridinyl)methyl]oxy}phenyl)-1,2,3,4-tetrahydroisoquinoline;

N-methyl-4-{[(4-methyl-2-pyridinyl)methyl]oxy}-3-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)benzamide;

4-{[(4-methyl-2-pyridinyl)methyl]oxy}-3-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)benzamide;

N,N-dimethyl-4-{[(4-methyl-2-pyridinyl)methyl]oxy}-3-(1,2,3,4-tetrahydro-7-isoquinolinyl)benzamide;

4-{[(4-methyl-2-pyridinyl)methyl]oxy}-3-(1,2,3,4-tetrahydro-7-isoquinolinyl)benzamide;

7-(2,3-bis(methyloxy)-6-{[(4-methyl-2-pyridinyl)methyl]oxy}phenyl)-1,2,3,4-tetrahydroisoquinoline;

7-(2,3-bis(methyloxy)-6-{[(4-methyl-2-pyridinyl)methyl]oxy}phenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine;

7-[2-({[4-(methyloxy)-2-pyridinyl]methyl}oxy)phenyl]-2,3,4,5-tetrahydro-1H-3-benzazepine;

1-[4-[(2-pyridinylmethyl)oxy]-3-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)phenyl]ethanone,trifluoroacetate;

7-{6-methyl-3-[(2-pyrazinylmethyl)oxy]-2-pyridinyl}-2,3,4,5-tetrahydro-1H-3-benzazepine,trifluoroacetate;

7-(6-methyl-3-{[(4-methyl-2-pyridinyl)methyl]oxy}-2-pyridinyl)-2,3,4,5-tetrahydro-1H-3-benzazepine,trifluoroacetate;

7-{5-(methyloxy)-2-[(2-pyrazinylmethyl)oxy]phenyl}-2,3,4,5-tetrahydro-1H-3-benzazepine,trifluoroacetate;

7-[5-(methyloxy)-2-({[4-(methyloxy)-2-pyridinyl]methyl}oxy)phenyl]-2,3,4,5-tetrahydro-1H-3-benzazepine;

7-(5-(methyloxy)-2-{[(4-methyl-2-pyridinyl)methyl]oxy}phenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine,trifluoroacetate;

1-[4-({[4-(methyloxy)-2-pyridinyl]methyl}oxy)-3-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)phenyl]ethanone;

1-[4-{[(4-methyl-2-pyridinyl)methyl]oxy}-3-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)phenyl]ethanone,trifluoroacetate;

7-[2-({[4-(methyloxy)-2-pyridinyl]methyl}oxy)phenyl]-2,3,4,5-tetrahydro-1H-3-benzazepine,trifluoroacetate;

1,1-dimethylethyl7-[6-methyl-3-({[4-(methyloxy)-2-pyridinyl]methyl}oxy)-2-pyridinyl]-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate;

7-(5-fluoro-2-{[(4-methyl-2-pyridinyl)methyl]oxy}phenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine;

7-(5-methyl-2-{[(4-methyl-2-pyridinyl)methyl]oxy}phenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine;

7-(5-(ethyloxy)-2-{[(4-methyl-2-pyridinyl)methyl]oxy}phenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine;

7-(5-(methyloxy)-2-{[(4-methyl-2-pyridinyl)methyl]oxy}phenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine;

4-{[(4-methyl-2-pyridinyl)methyl]oxy}-3-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)benzonitrile;

7-[2-{[(4-methyl-2-pyridinyl)methyl]oxy}-5-(trifluoromethyl)phenyl]-2,3,4,5-tetrahydro-1H-3-benzazepine;

7-(5-(1,1-dimethylethyl)-2-{[(4-methyl-2-pyridinyl)methyl]oxy}phenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine;

7-(5-chloro-2-{[(4-methyl-2-pyridinyl)methyl]oxy}phenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine;

7-(3-{[(4-ethyl-2-pyridinyl)methyl]oxy}-6-methyl-2-pyridinyl)-2,3,4,5-tetrahydro-1H-3-benzazepine;

7-(6-(1,1-dimethylethyl)-3-{[(4-methyl-2-pyridinyl)methyl]oxy}-2-pyridinyl)-2,3,4,5-tetrahydro-1H-3-benzazepine;

1-[4-{[(4-ethyl-2-pyridinyl)methyl]oxy}-3-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)phenyl]ethanone;

1-[4-({[4-(ethyloxy)-2-pyridinyl]methyl}oxy)-3-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)phenyl]ethanone;

1-[4-{[(4-{[2-(methyloxy)ethyl]oxy}-2-pyridinyl)methyl]oxy}-3-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)phenyl]ethanone;

7-{5-(methyloxy)-2-[(2-pyridinylmethyl)oxy]phenyl}-2,3,4,5-tetrahydro-1H-3-benzazepine;

1-[4-[(2-pyridinylmethyl)oxy]-3-(1,2,3,4-tetrahydro-7-isoquinolinyl)phenyl]ethanone;

7-{5-chloro-2-[(2-pyridinylmethyl)oxy]phenyl}-1,2,3,4-tetrahydroisoquinoline;

7-(6-chloro-3-{[(4-methyl-2-pyridinyl)methyl]oxy}-2-pyridinyl)-2,3,4,5-tetrahydro-1H-3-benzazepine;

7-(6-chloro-3-{[(4-methyl-2-pyridinyl)methyl]oxy}-2-pyridinyl)-1,2,3,4-tetrahydroisoquinoline;

1,1-dimethylethyl5-{5-acetyl-2-[(2-pyridinylmethyl)oxy]phenyl}-1,3-dihydro-2H-isoindole-2-carboxylate;

1-[4-[(2-pyridinylmethyl)oxy]-3-(1,2,3,4-tetrahydro-6-isoquinolinyl)phenyl]ethanone;and

7-{2-(methyloxy)-6-[(2-pyrazinylmethyl)oxy]phenyl}-2,3,4,5-tetrahydro-1H-3-benzazepine,hydrochloride; or a salt thereof.

In one embodiment, the compound of formula (I) is selected from:

7-(3-{[(4-methyl-2-pyridinyl)methyl]oxy}-2-pyridinyl)-2,3,4,5-tetrahydro-1H-3-benzazepine;

7-(2-(methyloxy)-6-{[(4-methyl-2-pyridinyl)methyl]oxy}phenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine;

7-(4-(methyloxy)-2-{[(4-methyl-2-pyridinyl)methyl]oxy}phenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine;

1-[4-{[(4-methyl-2-pyridinyl)methyl]oxy}-3-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)phenyl]ethanone;

1-[4-[(2-pyrazinylmethyl)oxy]-3-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)phenyl]ethanone;

7-(5-fluoro-2-{[(4-methyl-2-pyridinyl)methyl]oxy}phenyl)-1,2,3,4-tetrahydroisoquinoline;

7-[2-({[4-(methyloxy)-2-pyridinyl]methyl}oxy)phenyl]-2,3,4,5-tetrahydro-1H-3-benzazepine;and

1-[4-[(2-pyridinylmethyl)oxy]-3-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)phenyl]ethanone;

or a salt thereof.

In one embodiment the compound of formula (I) is:

7-(3-{[(4-methyl-2-pyridinyl)methyl]oxy}-2-pyridinyl)-2,3,4,5-tetrahydro-1H-3-benzazepine;

or a salt thereof.

In another embodiment the compound of formula (I) is:

7-(2-(methyloxy)-6-{[(4-methyl-2-pyridinyl)methyl]oxy}phenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine;

or a salt thereof.

In another embodiment the compound of formula (I) is:

7-(4-(methyloxy)-2-{[(4-methyl-2-pyridinyl)methyl]oxy}phenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine;

or a salt thereof.

In a further embodiment the compound of formula (I) is:

1-[4-{[(4-methyl-2-pyridinyl)methyl]oxy}-3-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)phenyl]ethanone;

or a salt thereof.

It will be appreciated in the following that the phrase “a compound offormula (I)” is intended to include a compound of formula (Ia).

It will be appreciated that compounds of formula (I) and salts thereofmay exist in solvated forms. In another embodiment, the presentinvention provides compounds of formula (I) and salts thereof. Inanother embodiment, the present invention provides compounds of formula(I) and pharmaceutically acceptable salts thereof. In anotherembodiment, the present invention provides compounds of formula (I) andsolvates thereof. In a further embodiment, the present inventionprovides compounds of formula (I) as the free base.

Compounds of the present invention are useful as inhibitors of Syk.

As used herein, the term “alkyl” refers to a straight or branchedsaturated hydrocarbon chain containing the specified number of carbonatoms. For example, C₁₋₆alkyl means a straight or branched alkyl groupcontaining at least 1, and at most 6, carbon atoms. Examples of “alkyl”as used herein include, but are not limited to, methyl, ethyl, n-propyl,n-butyl, n-pentyl, n-hexyl, isobutyl, isopropyl, t-butyl and1,1-dimethylpropyl.

As used herein, the term “alkoxy” refers to a straight or branchedsaturated alkoxy chain containing the specified number of carbon atoms.For example, C₁₋₆alkoxy means a straight or branched alkoxy groupcontaining at least 1, and at most 6, carbon atoms. Examples of “alkoxy”as used herein include, but are not limited to, methoxy, ethoxy,propoxy, prop-2-oxy, butoxy, but-2-oxy, 2-methylprop-1-oxy,2-methylprop-2-oxy, pentoxy or hexyloxy.

As used herein, the term “halo” or, alternatively, “halogen” refers tofluoro, chloro or bromo.

As used herein, the term “haloalkyl” refers to a straight or branchedsaturated hydrocarbon chain containing the specified number of carbonatoms, substituted with halo atoms. For example, Halo-C₁₋₆alkyl means astraight or branched alkyl group containing at least 1, and at most 6,carbon atoms, substituted with 1 to 3 halo atoms per carbon atom.Examples of “haloalkyl” as used herein include, but are not limited to,fluoromethyl, di-fluoromethyl, and tri-fluoromethyl.

As used herein, the term “pharmaceutically acceptable” refers to thosecompounds, materials, compositions, and dosage forms which are, withinthe scope of sound medical judgment, suitable for use in contact withthe tissues of human beings and animals without excessive toxicity,irritation, or other problems or complications, commensurate with areasonable benefit/risk ratio. The skilled artisan will appreciate thatpharmaceutically acceptable salts of the compound of Formula (I) may beprepared.

As used herein, the term “pharmaceutically acceptable salts” refers tosalts that retain the desired biological activity of the subjectcompound and exhibit minimal undesired toxicological effects. Thesepharmaceutically acceptable salts may be prepared in situ during thefinal isolation and purification of the compound, or by separatelyreacting the purified compound in its free acid or free base form with asuitable base or acid, respectively. Indeed, in certain embodiments ofthe invention, pharmaceutically acceptable salts may be preferred overthe respective free base or free acid because such salts impart greaterstability or solubility to the molecule thereby facilitating formulationinto a dosage form.

The compounds of formula (I) are basic and accordingly generally capableof forming pharmaceutically acceptable acid addition salts by treatmentwith a suitable acid. Suitable acids include pharmaceutically acceptableinorganic acids and pharmaceutically acceptable organic acids.Representative pharmaceutically acceptable acid addition salts includehydrochloride, hydrobromide, nitrate, methylnitrate, sulfate, bisulfate,sulfamate, phosphate, acetate, hydroxyacetate, phenylacetate,propionate, butyrate, isobutyrate, valerate, maleate, hydroxymaleate,acrylate, fumarate, malate, tartrate, citrate, salicylate,p-aminosalicyclate, glycollate, lactate, heptanoate, phthalate, oxalate,succinate, benzoate, o-acetoxybenzoate, chlorobenzoate, methylbenzoate,dinitrobenzoate, hydroxybenzoate, methoxybenzoate, mandelate, tannate,formate, stearate, ascorbate, palmitate, oleate, pyruvate, pamoate,malonate, laurate, glutarate, glutamate, estolate, methanesulfonate(mesylate), ethanesulfonate (esylate), 2-hydroxyethanesulfonate,benzenesulfonate (besylate), p-aminobenzenesulfonate, p-toluenesulfonate(tosylate), napthalene-2-sulfonate, Ethanedisulfonate, and 2,5-dihydroxybenzoate. In one embodiment, the present invention provides apharmaceutically acceptable salt of a compound of formula (I) which isthe hydrochloride salt, mesylate, fumarate or phosphate. In oneembodiment, the present invention provides a pharmaceutically acceptablesalt of a compound of formula (I) which is the mesylate.

A compound of formula (I) may exist in solid or liquid form. In thesolid state, the compound of formula (I) may exist in crystalline ornon-crystalline (amorphous) form, or as a mixture thereof. For acompound of formula (I) that is in crystalline form, the skilled artisanwill appreciate that solvates, such as pharmaceutically acceptablesolvates, may be formed wherein solvent molecules are incorporated intothe crystalline lattice during crystallization. Solvates may involvenon-aqueous solvents such as, but not limited to, ethanol, isopropanol,n-butanol, i-butanol, acetone, tetrahydrofuran, dioxane, DMSO, aceticacid, ethanolamine, and ethyl acetate, or they may involve water as thesolvent that is incorporated into the crystalline lattice. Solvateswherein water is the solvent incorporated into the crystalline latticeare typically referred to as “hydrates”. Hydrates include stoichiometrichydrates as well as compositions containing variable amounts of water.

The skilled artisan will further appreciate that a compound of formula(I) that exists in crystalline form, including the various solvatesthereof, may exhibit polymorphism (i.e. the capacity to occur indifferent crystalline structures). These different crystalline forms aretypically known as “polymorphs.” The invention includes all suchpolymorphs. Polymorphs have the same chemical composition but differ inpacking, geometrical arrangement, and other descriptive properties ofthe crystalline solid state. Polymorphs, therefore, may have differentphysical properties such as shape, density, hardness, deformability,stability and dissolution properties. Polymorphs typically exhibitdifferent melting points, IR spectra, and X-ray powder diffractionpatterns, which may be used for identification. The skilled artisan willappreciate that different polymorphs may be produced, for example, bychanging or adjusting the reaction conditions or reagents, used inmaking the compound. For example, changes in temperature, pressure, orsolvent may result in polymorphs. In addition, one polymorph mayspontaneously convert to another polymorph under certain conditions.

In a further aspect, the present invention provides a crystalline formof7-(2-(methyloxy)-6-{[(4-methyl-2-pyridinyl)methyl]oxy}phenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine(FORM 1) characterised by substantially the same X-ray powderdiffraction (XRPD) pattern as shown in FIG. 1, wherein the XRPD patternis expressed in terms of 2 theta angles and obtained with adiffractometer using copper Kα-radiation using procedures describedherein. The XRPD of FORM 1 shows characteristic 2 theta angle peaks at11.7, 12.7, 13.7 and 16.0.

Alternatively or additionally, FORM 1 of7-(2-(methyloxy)-6-{[(4-methyl-2-pyridinyl)methyl]oxy}phenyl)-2, 3,4,5-tetrahydro-1H-3-benzazepine can be characterised by Raman spectroscopyas shown in FIG. 2, wherein the spectrum is expressed in terms of cm⁻¹and obtained using procedures as herein described. The Raman spectrum ofFORM 1 has characteristic peaks at 2945, 2832, 1610, 1363, 994 and 784.

Alternatively or additionally, FORM 1 of7-(2-(methyloxy)-6-{[(4-methyl-2-pyridinyl)methyl]oxy}phenyl)-2,3,4,5-tetrahydro-1H-3-benzazepinecan be characterised by differential scanning calorimitry (DSC)thermograms as shown in FIG. 3, wherein the DSC was performed usingprocedures as herein described.

In a further aspect, the present invention provides a crystalline formof7-(2-(methyloxy)-6-{[(4-methyl-2-pyridinyl)methyl]oxy}phenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine(FORM 2) characterised by substantially the same X-ray powderdiffraction (XRPD)pattern as shown in FIG. 4, wherein the XRPD patternis expressed in terms of 2 theta angles and obtained with adiffractometer using copper Kα-radiation using procedures describedherein. The XRPD of FORM 1 shows characteristic 2 theta angle peaks at8.9, 9.9, 13.3, 15.2, 16.7.

Alternatively or additionally, FORM 2 of7-(2-(methyloxy)-6-{[(4-methyl-2-pyridinyl)methyl]oxy}phenyl)-2, 3,4,5-tetrahydro-1H-3-benzazepine can be characterised by Raman spectroscopyas shown in FIG. 5, wherein the spectrum is expressed in terms of cm⁻¹and obtained using procedures as herein described. The Raman spectrum ofFORM 1 has characteristic peaks at 2934, 1614, 1371, 1005 and 777.

Alternatively or additionally, FORM 2 of7-(2-(methyloxy)-6-{[(4-methyl-2-pyridinyl)methyl]oxy}phenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine can becharacterised by differential scanning calorimitry (DSC) thermograms asshown in FIG. 6, wherein the DSC was performed using methods asdescribed herein.

A compound of formula (I) may be prepared by the general syntheticschemes described hereinafter.

wherein Y, R₁ and R₂ are as hereinbefore defined.

-   Step A: Potassium carbonate/DMF-   Step B: PdCl₂.dppf/caesium carbonate/aqueous dioxane/heat; or    -   tetrakis/sodium carbonate/aqueous DME/heat-   Step C: HCl in dioxane; or    -   trifluoroacetic acid in dichloromethane

Thus, in a further aspect, the present invention provides a process forpreparing a compound of formula (I) which process comprises reacting acompound of formula (II):

wherein X, Y and R₂ are as hereinbefore defined;

with a boronic ester or acid of formula (III):

wherein R₆ and R₇ which may be the same or different are each hydrogen,C₁₋₆alkyl or R₆ and R₇ may be joined to form a C₁₋₃alkylene groupoptionally substituted by up to four methyl groups, for instance—C(Me)₂C(Me)₂—;

P is a protecting group; and

m and n are as hereinbefore defined;

in the presence of a catalyst, under conditions typically used for aboronic ester/acid coupling; and

thereafter, removing any protecting group.

Conditions typically used for a boronic ester/acid coupling includes theuse of the Pd(PPh₃)₄ as catalyst, with caesium carbonate in a solventsuch as aqueous 1,4-dioxane. Alternatively conditions that could be usedinclude the use of PEPPSI™ as catalyst, with potassium hydroxide in asolvent such as aqueous dimethoxyethane (DME) with ethanol.

Examples of protecting groups and the means for their removal can befound in T. W. Greene ‘Protective Groups in Organic Synthesis’ (J. Wileyand Sons, 1991). Suitable amine protecting groups include, but are notrestricted to, sulphonyl (such as tosyl), acyl (such asbenzyloxycarbonyl or t-butoxycarbonyl) and arylalkyl (such as benzyl),which may be removed by hydrolysis or hydrogenolysis as appropriate.Other suitable amine protecting groups include trifluoroacetyl(—C(O)CF₃), which may be removed by base catalysed hydrolysis, or asolid phase resin bound benzyl group, such as a Merrifield resin bound2,6-dimethoxybenzyl group (Ellman linker) which may be removed by acidcatalysed hydrolysis (using, for example, trifluoroacetic acid).

In one embodiment of the present invention the protecting group (P) isselected from tert-butyloxycarbonyl “BOC” and9-fluorenylmethyloxycarbonyl “FmoC”.

Compounds of formula (I) are useful as inhibitors of Syk and thuspotentially of use in treating some cancer therapies, in particular hememalignancies, as well as inflammatory conditions which involve B cells,and also diseases resulting from inappropriate mast cell activation, forinstance allergic and inflammatory diseases such as cutaneous mast cellmediated diseases including acute and chronic urticaria, mastocytosis,atopic dermatitis and autoimmune diseases such as cutaneous lupus andautoimmune bullous conditions including pemphigus and pemphigoid.

In one aspect, the present invention provides a compound of formula (I)or a pharmaceutically acceptable salt thereof, for use in therapy.

In another aspect, the present invention provides a compound of formula(I) or a pharmaceutically acceptable salt thereof, for use in inhibitingspleen tyrosine kinase (Syk).

In a further aspect, the present invention provides a method comprisingadministering to a subject, particularly a human subject in need thereofan effective amount of a compound of formula (I) or a pharmaceuticallyacceptable salt thereof, to inhibit a spleen tyrosine kinase (Syk).

Syk inhibitors may be useful in cancer therapy, specifically hememalignancies, particularly Non-Hodgkin's Lymphomas including follicular(FL), mantle cell, small lymphocytic lymphoma/chronic lymphocyticlymphoma (SLL/CLL), Burkitt and diffuse large B cell (DLBCL) lymphomas.Syk inhibitors may also be useful in the treatment of Acute myeloidleukaemia and retinoblastoma.

In one aspect, the present invention provides a compound of formula (I)or a pharmaceutically acceptable salt thereof, for use in the treatmentof cancer, for example, Acute myeloid leukaemia, retinoblastoma, hememalignancies, particularly Non-Hodgkin's lymphomas including follicular(FL), mantle cell, small lymphocytic lymphoma/chronic lymphocyticlymphoma (SLL/CLL), Burkitt and diffuse large B cell (DLBCL) lymphomas.

In another aspect, the present invention provides a method of treatingcancer, for example, Acute myeloid leukaemia, retinoblastoma, hememalignancies, particularly Non-Hodgkin's Lymphomas including follicular(FL), mantle cell, small lymphocytic lymphoma/chronic lymphocyticlymphoma (SLL/CLL), Burkitt and diffuse large B cell (DLBCL) lymphomas,which method comprises administering to a subject, particularly a humansubject in need thereof a therapeutically effective amount of a compoundof formula (I) or a pharmaceutically acceptable salt thereof.

In a further aspect, the present invention provides the use of acompound of formula (I) or a pharmaceutically acceptable salt thereof,for the manufacture of a medicament for the treatment of cancer, forexample, Acute myeloid leukaemia, retinoblastoma, heme malignancies,particularly Non-Hodgkin's lymphomas including follicular (FL), mantlecell, small lymphocytic lymphoma/chronic lymphocytic lymphoma (SLL/CLL),Burkitt and diffuse large B cell (DLBCL) lymphomas.

Compounds of formula (I) may also be used in cancer chemotherapy incombination with other classes of cancer chemotherapy agents which areknown in the art. Representative classes of agents for use in suchcombinations for Non-Hodgkin's Lymphomas include rituximab, BEXXAR(tositumomab and Iodine I 131 tositumomab) and pixantrone. Compounds ofthe Formula (I) may also be used in combination with the CHOP drugregime (cyclophosphamide, adriamycin, vincristine, prednisone) or CHOPplus rituximab (CHOP+R).

Compounds of formula (I) are potentially of use in treating autoimmuneconditions which involve B cells and/or macrophage activation, forexample systemic lupus erythematosus (SLE), discoid (cutaneous) lupus,Sjorgens syndrome, Wegners granulomatosis and other vasculitides,bullous pemphigoid and pemphigus, idiopathic thrombocytopenic purpura(ITP), giant cell arteriosis, chronic idiopathic urticaria with andwithout auto-antibody status (chronic autoimmune urticaria (New conceptsin chronic urticaria, Current Opinions in Immunology 2008 20:709-716)),glomerulonephritis, chronic transplant rejection, and rheumatoidarthritis.

In one aspect, the present invention provides a compound of formula (I)or a pharmaceutically acceptable salt thereof, for use in the treatmentof an autoimmune condition, for example systemic lupus erythematosus(SLE), discoid (cutaneous) lupus, Sjorgens syndrome, Wegnersgranulomatosis and other vasculitides, bullous pemphigoid and pemphigus,idiopathic thrombocytopenic purpura (ITP), giant cell arteriosis,chronic idiopathic urticaria with and without auto-antibody status(chronic autoimmune urticaria (New concepts in chronic urticaria,Current Opinions in Immunology 2008 20:709-716)), glomerulonephritis,chronic transplant rejection, and rheumatoid arthritis. In oneembodiment, the present invention provides a compound of formula (I) ora pharmaceutically acceptable salt thereof for use in the treatment ofan autoimmune condition which is chronic idiopathic urticaria with andwithout auto-antibody status. In another embodiment, the presentinvention provides a compound of formula (I) or a pharmaceuticallyacceptable salt thereof for use in the treatment of an autoimmunecondition which is discoid (cutaneous) lupus.

In another aspect, the present invention provides a method of treatingan autoimmune condition, for example systemic lupus erythematosus (SLE),discoid (cutaneous) lupus, Sjorgens syndrome, Wegners granulomatosis andother vasculitides, bullous pemphigoid and pemphigus, idiopathicthrombocytopenic purpura (ITP), giant cell arteriosis, chronicidiopathic urticaria with and without auto-antibody status,glomerulonephritis, chronic transplant rejection and rheumatoidarthritis, which method comprises administering to a subject,particularly a human subject in need thereof a therapeutically effectiveamount of a compound of formula (I) or a pharmaceutically acceptablesalt thereof. In one embodiment, the present invention provides a methodof treating an autoimmune disease which is chronic idiopathic urticariawith and without auto-antibody status, which method comprisesadministering to a subject, particularly a human subject in need thereofa therapeutically effective amount of a compound of formula (I) or apharmaceutically acceptable salt thereof. In another embodiment, thepresent invention provides a method of treating an autoimmune diseasewhich is discoid (cutaneous) lupus, which method comprises administeringto a subject, particularly a human subjectin need thereof atherapeutically effective amount of a compound of formula (I) or apharmaceutically acceptable salt thereof.

In a further aspect, the present invention provides the use of acompound of formula (I) or a pharmaceutically acceptable salt thereof,for the manufacture of a medicament for the treatment of an autoimmunecondition, for example systemic lupus erythematosus (SLE), discoid(cutaneous) lupus, Sjorgens syndrome, Wegners granulomatosis and othervasculitides, bullous pemphigoid and pemphigus, idiopathicthrombocytopenic purpura (ITP), giant cell arteriosis, chronicidiopathic urticaria with and without auto-antibody status,glomerulonephritis, chronic transplant rejection and rheumatoidarthritis. In one embodiment, the present invention provides the use ofa compound of formula (I) or a pharmaceutically acceptable salt thereoffor the manufacture of a medicament for the treatment of an autoimmunecondition which is chronic idiopathic urticaria with and withoutauto-antibody status. In another embodiment, the present inventionprovides the use of a compound of formula (I) or a pharmaceuticallyacceptable salt thereof for the manufacture of a medicament for thetreatment of an autoimmune condition which is discoid (cutaneous) lupus.

In one aspect, the present invention provides a compound of formula (I)or a pharmaceutically acceptable salt thereof, for use in the treatmentof an inflammatory disease which involves B cells.

In another aspect, the present invention provides a method of treatingan inflammatory disease which involves B cells which method comprisesadministering to a subject, particularly a human subject in need thereofa therapeutically effective amount of a compound of formula (I) or apharmaceutically acceptable salt thereof.

In a further aspect, the present invention provides the use of acompound of formula (I) or a pharmaceutically acceptable salt thereof,for the manufacture of a medicament for the treatment of an inflammatorydisease which involves B cells.

Compounds of formula (I) are potentially of use in treating diseasesresulting from inappropriate mast cell activation, for instance allergicand inflammatory diseases particularly with skin manifestations.

In one aspect, the present invention provides a compound of formula (I)or a pharmaceutically acceptable salt thereof, for use in the treatmentof a disease associated with inappropriate mast cell activation.

In another aspect, the present invention provides a method of treating adisease associated with inappropriate mast cell activation which methodcomprises administering to a subject, particularly a human subject inneed thereof a therapeutically effective amount of a compound of formula(I) or a pharmaceutically acceptable salt thereof.

In a further aspect, the present invention provides the use of acompound of formula (I) or a pharmaceutically acceptable salt thereof,for the manufacture of a medicament for the treatment of a diseaseassociated with inappropriate mast cell activation.

In one aspect, the present invention provides a compound of formula (I)or a pharmaceutically acceptable salt thereof, for use in the treatmentof an inflammatory disease and/or allergic disorder for example, chronicobstructive pulmonary disease (COPD), adult respiratory distresssyndrome (ARDS), asthma, severe asthma, ulcerative colitis, Crohn'sdisease, bronchitis, conjunctivitis, psoriasis, scleroderma, dermatitis,allergy, rhinitis, cutaneous lupus, autoimmune bullous conditionsincluding pemphigus and pemphigoid, mastocytosis and anaphylaxis.

In another aspect, the present invention provides a method of treatingan inflammatory disease and/or allergic disorder for example, chronicobstructive pulmonary disease (COPD), adult respiratory distresssyndrome (ARDS), asthma, severe asthma, ulcerative colitis, Crohn'sdisease, bronchitis, conjunctivitis, psoriasis, scleroderma, dermatitis,allergy, rhinitis, cutaneous lupus, autoimmune bullous conditionsincluding pemphigus and pemphigoid, mastocytosis and anaphylaxis, whichmethod comprises administering to a subject, particularly a humansubject in need thereof a therapeutically effective amount of a compoundof formula (I)or a pharmaceutically acceptable salt thereof.

In a further aspect, the present invention provides the use of acompound of formula (I) or a pharmaceutically acceptable salt thereof,for the manufacture of a medicament for the treatment of an inflammatorydisease and/or allergic disorder for example, chronic obstructivepulmonary disease (COPD), adult respiratory distress syndrome (ARDS),asthma, severe asthma, ulcerative colitis, Crohn's disease, bronchitis,conjunctivitis, psoriasis, scleroderma, dermatitis, allergy, rhinitis,cutaneous lupus, autoimmune bullous conditions including pemphigus andpemphigoid, mastocytosis and anaphylaxis.

Compounds of formula (I) may also be used in combination with otherclasses of therapeutic agents, for example selected fromanti-inflammatory agents, anticholinergic agents (particularly anM₁/M₂/M₃ receptor antagonist), β₂-adrenoreceptor agonists, antiinfectiveagents such as antibiotics or antivirals, or antihistamines.

In another embodiment, compounds of formula (I) may be used incombination with other classes of therapeutic agents which are known inthe art for treating autoimmune diseases, for instance disease modifyinganti-rheumatic drugs including cyclosporine, methotrexate,sulphasalazine, prednisone, leflunomide, andchloroquine/hydrochloroquine and also biopharmaceutical agents such ashumanised monoclonal antibodies (mabs), for example including anti-TNFalpha blockers such as remicade, enbrel and humira, B cell depletingtherapies such as rituximab and ofatumumab, and anti-Blys mabs such asbelilumab.

The invention thus provides, a combination comprising a compound offormula (I) or a pharmaceutically acceptable salt thereof together withone or more other therapeutically active agents, for example selectedfrom an anti-inflammatory agent such as a corticosteroid or an NSAID, ananticholinergic agent, a β₂-adrenoreceptor agonist, an antiinfectiveagent such as an antibiotic or an antiviral, an antihistamine, a diseasemodifying anti-rheumatic drug, and a biopharmaceutical agent such ashumanised monoclonal antibodies (mabs), B cell depleting therapies andanti-Blys mabs. One embodiment of the invention encompasses combinationscomprising a compound of formula (I) or a pharmaceutically acceptablesalt thereof together with a β₂-adrenoreceptor agonist, and/or ananticholinergic, and/or a PDE-4 inhibitor, and/or an antihistamine,and/or a disease modifying anti-rheumatic drug, and/or abiopharmaceutical agent.

One embodiment of the invention encompasses combinations comprising oneor two other therapeutically active agents.

It will be clear to a person skilled in the art that, where appropriate,the other therapeutic ingredient(s) may be used in the form of salts,for example as alkali metal or amine salts or as acid addition salts, orprodrugs, or as esters, for example lower alkyl esters, or as solvates,for example hydrates to optimise the activity and/or stability and/orphysical characteristics, such as solubility, of the therapeuticingredient. It will be clear also that, where appropriate, thetherapeutic ingredients may be used in optically pure form.

Examples of β₂-adrenoreceptor agonists include salmeterol (which may bea racemate or a single enantiomer such as the R-enantiomer), salbutamol(which may be a racemate or a single enantiomer such as theR-enantiomer), formoterol (which may be a racemate or a singlediastereomer such as the R,R-diastereomer), salmefamol, fenoterol,carmoterol, etanterol, naminterol, clenbuterol, pirbuterol, flerbuterol,reproterol, bambuterol, indacaterol, terbutaline and salts thereof, forexample the xinafoate (1-hydroxy-2-naphthalenecarboxylate) salt ofsalmeterol, the sulphate salt or free base of salbutamol or the fumaratesalt of formoterol. In one embodiment the β₂-adrenoreceptor agonists arelong-acting β₂-adrenoreceptor agonists, for example, compounds whichprovide effective bronchodilation for about 12 hours or longer.

Other β₂-adrenoreceptor agonists include those described in WO02/066422,WO02/070490, WO02/076933, WO03/024439, WO03/072539, WO03/091204,WO04/016578, WO04/022547, WO04/037807, WO04/037773, WO04/037768,WO04/039762, WO04/039766, WO01/42193 and WO03/042160.

Examples of β₂-adrenoreceptor agonists include:

3-(4-{[6-{(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl) benzenesulfonamide;

3-(3-{[7-({(2R)-2-hydroxy-2-[4-hydroxy-3-hydroxymethyl)phenyl]ethyl}-amino) heptyl]oxy}propyl) benzenesulfonamide;

4-{(1R)-2-[(6-{2-[(2,6-dichlorobenzyl) oxy]ethoxy}hexyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl) phenol;

4-{(1R)-2-[(6-{4-[3-(cyclopentylsulfonyl)phenyl]butoxy}hexyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol;

N-[2-hydroxyl-5-[(1R)-1-hydroxy-2-[[2-4-[[(2R)-2-hydroxy-2-phenylethyl]amino]phenyl]ethyl]amino]ethyl]phenyl]formamide;

N-2{2-[4-(3-phenyl-4-methoxyphenyl)aminophenyl]ethyl}-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;and

5-[(R)-2-(2-{4-[4-(2-amino-2-methyl-propoxy)-phenylamino]-phenyly}-ethylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one.

The β₂-adrenoreceptor agonist may be in the form of a salt formed with apharmaceutically acceptable acid selected from sulphuric, hydrochloric,fumaric, hydroxynaphthoic (for example 1- or 3-hydroxy-2-naphthoic),cinnamic, substituted cinnamic, triphenylacetic, sulphamic, sulphanilic,naphthaleneacrylic, benzoic, 4-methoxybenzoic, 2- or 4-hydroxybenzoic,4-chlorobenzoic and 4-phenylbenzoic acid.

Examples of corticosteroids may include those described in WO02/088167,WO02/100879, WO02/12265, WO02/12266, WO05/005451, WO05/005452,WO06/072599 and WO06/072600.

Anti-inflammatory corticosteroids are well known in the art.Representative examples include fluticasone propionate (e.g. see U.S.Pat. No. 4,335,121), fluticasone furoate (e.g. see U.S. Pat. No.7,101,866), beclomethasone 17-propionate ester, beclomethasone17,21-dipropionate ester, dexamethasone or an ester thereof, mometasoneor an ester thereof (e.g. mometasone furoate), ciclesonide, budesonide,flunisolide, methyl prednisolone, prednisolone, dexamethasone and 6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-(2,2,3,3-tetramethycyclopropylcarbonyl)oxy-androsta-1,4-diene-17β-carbothioicacid S-cyanomethyl ester. Further examples of anti-inflammatorycorticosteroids are described in WO02/088167, WO02/100879, WO02/12265,WO02/12266, WO05/005451, WO05/005452, WO06/072599 and WO06/072600.

Non-steroidal compounds having glucocorticoid agonism that may possessselectivity for transrepression over transactivation and that may beuseful in combination therapy include those covered in the followingpublished patent applications and patents: WO03/082827, WO98/54159,WO04/005229, WO04/009017, WO04/018429, WO03/104195, WO03/082787,WO03/082280, WO03/059899, WO03/101932, WO02/02565, WO01/16128,WO00/66590, WO03/086294, WO04/026248, WO03/061651, WO03/08277,WO06/000401, WO06/000398, WO06/015870, WO06/108699, WO07/000334 andWO07/054294.

Examples of anti-inflammatory agents include non-steroidalanti-inflammatory drugs (NSAID's).

Examples of NSAID's include sodium cromoglycate, nedocromil sodium,phosphodiesterase (PDE) inhibitors (for example, theophylline, PDE4inhibitors or mixed PDE3/PDE4 inhibitors), leukotriene antagonists,inhibitors of leukotriene synthesis (for example montelukast), iNOSinhibitors, tryptase and elastase inhibitors, beta-2 integrinantagonists and adenosine receptor agonists or antagonists (e.g.adenosine 2a agonists), cytokine antagonists (for example chemokineantagonists, such as a CCR3 antagonist) or inhibitors of cytokinesynthesis, or 5-lipoxygenase inhibitors. An iNOS (inducible nitric oxidesynthase inhibitor) is preferably for oral administration. Examples ofiNOS inhibitors include those disclosed in WO93/13055, WO98/30537,WO02/50021, WO95/34534 and WO99/62875. Examples of CCR3 inhibitorsinclude those disclosed in WO02/26722.

Examples of PDE4 inhibitors includecis-4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-carboxylicacid,2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-oneandcis-[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-ol].Also,cis-4-cyano-4-[3-(cyclopentyloxy)-4-methoxyphenyl]cyclohexane-1-carboxylicacid (also known as cilomilast) and its salts, esters, pro-drugs orphysical forms (e.g. see U.S. Pat. No. 5,552,438).

Other compounds include AWD-12-281 from Elbion (Hofgen, N. et al. 15thEFMC Int Symp Med Chem (September 6-10, Edinburgh) 1998, Abst P.98; CASreference No. 247584020-9); a 9-benzyladenine derivative nominatedNCS-613 (INSERM); D-4418 from Chiroscience and Schering-Plough; abenzodiazepine PDE4 inhibitor identified as Cl-1018 (PD-168787) andattributed to Pfizer; a benzodioxole derivative disclosed by Kyowa Hakkoin WO99/16766; K-34 from Kyowa Hakko; V-11294A from Napp (Landells, L.J. et al. Eur Resp J [Annu Cong Eur Resp Soc (September 19-23, Geneva)1998] 1998, 12 (Suppl. 28): Abst P2393); roflumilast (CAS reference No162401-32-3) and a pthalazinone (e.g. see WO99/47505) from Byk-Gulden;Pumafentrine, (-)-p-[(4aR*, 10bS*)-9-ethoxy-1,2,3,4,4a,10b-hexahydro-8-methoxy-2-methylbenzo[c][1,6]naphthyridin-6-yl]-N,N-diisopropylbenzamidewhich is a mixed PDE3/PDE4 inhibitor which has been prepared andpublished on by Byk-Gulden, now Altana; arofylline under development byAlmirall-Prodesfarma; VM554/UM565 from Vernalis; or T-440 (TanabeSeiyaku; Fuji, K. et al. J Pharmacol Exp Ther,1998, 284(1): 162), andT2585.

Further compounds are disclosed in the published international patentapplication WO04/024728 (Glaxo Group Ltd), WO04/056823 (Glaxo Group Ltd)and WO04/103998 (Glaxo Group Ltd).

Examples of anticholinergic agents are those compounds that act asantagonists at the muscarinic receptors, in particular those compoundswhich are antagonists of the M₁ or M₃ receptors, dual antagonists of theM₁/M₃ or M₂/M₃, receptors or pan-antagonists of the M₁/M₂/M₃ receptors.Exemplary compounds for administration via inhalation includeipratropium (for example, as the bromide, CAS 22254-24-6, sold under thename Atrovent), oxitropium (for example, as the bromide, CAS 30286-75-0)and tiotropium (for example, as the bromide, CAS 136310-93-5, sold underthe name Spiriva). Also of interest are revatropate (for example, as thehydrobromide, CAS 262586-79-8) and LAS-34273 which is disclosed inWO01/04118. Exemplary compounds for oral administration includepirenzepine (CAS 28797-61-7), darifenacin (CAS 133099-04-4, or CAS133099-07-7 for the hydrobromide sold under the name Enablex),oxybutynin (CAS 5633-20-5, sold under the name Ditropan), terodiline(CAS 15793-40-5), tolterodine (CAS 124937-51-5, or CAS 124937-52-6 forthe tartrate, sold under the name Detrol), otilonium (for example, asthe bromide, CAS 26095-59-0, sold under the name Spasmomen), trospiumchloride (CAS 10405-02-4) and solifenacin (CAS 242478-37-1, or CAS242478-38-2 for the succinate also known as YM-905 and sold under thename Vesicare).

Other anticholinergic agents include compounds which are disclosed inU.S. patent application No. 60/487981 including, for example:

(3-endo)-3-(2,2-di-2-thienylethenyl)-8,8-dimethyl-8-azoniabicyclo[3.2.1]octanebromide;

(3-endo)-3-(2,2-diphenylethenyl)-8,8-dimethyl-8-azoniabicyclo[3.2.1]octanebromide;

(3-endo)-3-(2,2-diphenylethenyl)-8,8-dimethyl-8-azoniabicyclo[3.2.1]octane4-methylbenzenesulfonate;

(3-endo)-8,8-dimethyl-3-[2-phenyl-2-(2-thienyl)ethenyl]-8-azoniabicyclo[3.2.1]octanebromide; and

(3-endo)-8, 8-dimethyl-3-[2-phenyl-2-(2-pyridinyl)ethenyl]-8-azoniabicyclo[3.2.1]octanebromide.

Further anticholinergic agents include compounds which are disclosed inU.S. patent application No. 60/511009 including, for example:

(endo)-3-(2-methoxy-2,2-di-thiophen-2-yl-ethyl)-8,8-dimethyl-8-azonia-bicyclo[3.2.1]octaneiodide;

3-((endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl-propionitrile;

(endo)-8-methyl-3-(2,2,2-triphenyl-ethyl)-8-aza-bicyclo[3.2.1]octane;

3-((endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl-propionamide;

3-((endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl-propionicacid;

(endo)-3-(2-cyano-2,2-diphenyl-ethyl)-8,8-dimethyl-8-azonia-bicyclo[3.2.1]octaneiodide;

(endo)-3-(2-cyano-2,2-diphenyl-ethyl)-8,8-dimethyl-8-azonia-bicyclo[3.2.1]octanebromide;

3-((endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl-propan-1-ol;

N-benzyl-3-((endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl-propionamide;

(endo)-3-(2-carbamoyl-2,2-diphenyl-ethyl)-8,8-dimethyl-8-azonia-bicyclo[3.2.1]octaneiodide;

1-benzyl-3-[3-((endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl-propyl]-urea;

1-ethyl-3-[3-((endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl-propyl]-urea;

N-[3-((endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl-propyl]-acetamide;

N-[3-((endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl-propyl]-benzamide;

3-((endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-di-thiophen-2-yl-propionitrile;

(endo)-3-(2-cyano-2,2-di-thiophen-2-yl-ethyl)-8,8-dimethyl-8-azonia-bicyclo[3.2.1]octaneiodide;

N-[3-((endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl-propyl]-benzenesulfonamide;

[3-((endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl-propyl]-urea;

N-[3-((endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl-propyl]-methanesulfonamide;and

(endo)-3-{2,2-diphenyl-3-[(1-phenyl-methanoyl)-amino]-propyl}-8,8-dimethyl-8-azonia-bicyclo[3.2.1]octanebromide.

Further compounds include:

(endo)-3-(2-methoxy-2,2-di-thiophen-2-yl-ethyl)-8,8-dimethyl-8-azonia-bicyclo[3.2.1]octaneiodide;

(endo)-3-(2-cyano-2,2-diphenyl-ethyl)-8,8-dimethyl-8-azonia-bicyclo[3.2.1]octaneiodide;

(endo)-3-(2-cyano-2,2-diphenyl-ethyl)-8,8-dimethyl-8-azonia-bicyclo[3.2.1]octanebromide;

(endo)-3-(2-carbamoyl-2,2-diphenyl-ethyl)-8,8-dimethyl-8-azonia-bicyclo[3.2.1]octaneiodide;

(endo)-3-(2-cyano-2,2-di-thiophen-2-yl-ethyl)-8,8-dimethyl-8-azonia-bicyclo[3.2.1]octane iodide; and

(endo)-3-{2,2-diphenyl-3-[(1-phenyl-methanoyl)-amino]-propyl}-8,8-dimethyl-8-azonia-bicyclo[3.2.1]octanebromide.

In one embodiment the invention provides a combination comprising acompound of formula (I), or a pharmaceutically acceptable salt thereof,together with an H1 antagonist. Examples of H1 antagonists include,without limitation, methapyrilene, desloratadine, amelexanox,astemizole, azatadine, azelastine, acrivastine, brompheniramine,cetirizine, levocetirizine, efletirizine, chlorpheniramine, clemastine,cyclizine, carebastine, cyproheptadine, carbinoxamine,descarboethoxyloratadine, doxylamine, dimethindene, ebastine,epinastine, efletirizine, fexofenadine, hydroxyzine, ketotifen,loratadine, levocabastine, mizolastine, mequitazine, mianserin,noberastine, meclizine, norastemizole, olopatadine, picumast,pyrilamine, promethazine, terfenadine, tripelennamine, temelastine,trimeprazine and triprolidine, particularly cetirizine, levocetirizine,efletirizine and fexofenadine. In a further embodiment the inventionprovides a combination comprising a compound of formula (I), or apharmaceutically acceptable salt thereof, together with an H3 antagonist(and/or inverse agonist). Examples of H3 antagonists include, forexample, those compounds disclosed in WO2004/035556 and inWO2006/045416. Other histamine receptor antagonists which may be used incombination with the compounds of formula (I), or a pharmaceuticallyacceptable salt thereof, include antagonists (and/or inverse agonists)of the H4 receptor, for example, the compounds disclosed in Jablonowskiet al., J. Med. Chem. 46:3957-3960 (2003).

In one embodiment there is provided, a combination comprising a compoundof formula (I) or a pharmaceutically acceptable salt thereof togetherwith a corticosteroid. In another embodiment there is provided, acombination comprising a compound of formula (I) or a pharmaceuticallyacceptable salt thereof together with an NSAID. In another embodimentthere is provided, a combination comprising a compound of formula (I) ora pharmaceutically acceptable salt thereof together with ananticholinergic. In another embodiment there is provided, a combinationcomprising a compound of formula (I) or a pharmaceutically acceptablesalt thereof together with a β₂-adrenoreceptor agonist. In anotherembodiment there is provided, a combination comprising a compound offormula (I) or a pharmaceutically acceptable salt thereof together withan antiinfective. In another embodiment there is provided, a combinationcomprising a compound of formula (I) or a pharmaceutically acceptablesalt thereof together with an antihistamine. In another embodiment thereis provided, a combination comprising a compound of formula (I) or apharmaceutically acceptable salt thereof together with a diseasemodifying anti-rheumatic drug. In a further embodiment there isprovided, a combination comprising a compound of formula (I) or apharmaceutically acceptable salt thereof together with abiopharmaceutical agent.

A compound of formula (I) will normally, but not necessarily, beformulated into pharmaceutical compositions prior to administration to apatient. Accordingly, in another aspect the invention is directed topharmaceutical compositions comprising a compound of formula (I), or apharmaceutically acceptable salt thereof, and one or morepharmaceutically acceptable carriers, diluents or excipients.

The pharmaceutical compositions of compounds of formula (I) may beprepared and packaged in bulk form wherein a safe and effective amountof a compound of the formula (I) can be extracted and then given to thepatient, such as with powders or syrups. Alternatively, thepharmaceutical compositions of compounds of formula (I) may be preparedand packaged in unit dosage form wherein each physically discrete unitcontains a safe and effective amount of a compound of the formula (I).The pharmaceutical compositions of compounds of formula (I) may also beprepared and packaged in a sub-unit dosage form wherein two or moresub-unit dosage forms provide the unit dosage form. When prepared inunit dosage form, the pharmaceutical compositions of compounds offormula (I) typically contain from about 0.1 to 99.9 wt. %, of thecompound of formula (I), depending on the nature of the formulation.

In addition, the pharmaceutical compositions of compounds of formula (I)may optionally further comprise one or more additional therapeuticallyactive compounds.

As used herein, “pharmaceutically acceptable excipient” means apharmaceutically acceptable material, composition or vehicle involved ingiving form or consistency to the pharmaceutical composition. Eachexcipient must be compatible with the other ingredients of thepharmaceutical composition when commingled, such that interactions whichwould substantially reduce the efficacy of the compound of formula (I)when administered to a patient and would result in pharmaceuticallyunacceptable compositions are avoided. In addition, each excipient mustof course be of sufficiently high purity to render it pharmaceuticallyacceptable.

Compositions comprising a compound of formula (I), or a pharmaceuticallyacceptable salt thereof and one or more pharmaceutically acceptablecarriers, diluents or excipients will typically be provided as a dosageform adapted for administration to the patient by the desired route ofadministration. For example, dosage forms include those adapted for: (1)oral administration, such as tablets, capsules, caplets, pills, troches,powders, syrups, elixers, suspensions, solutions, emulsions, sachets,and cachets; (2) topical dermal administration, such as creams,ointments, lotions, solutions, pastes, sprays, foams, and gels, (3)inhalation, such as aerosols and solutions; (4) intranasaladministration, such as solutions or sprays; (5) parenteraladministration, such as sterile solutions, suspensions, and powders forreconstitution and (6) intravitreal administration.

In one embodiment there is provided a dosage form adapted for topicaldermal administration.

It will be appreciated that dosage forms adapted for oral administrationare commonly used for treating autoimmune disease including rheumatoidarthritis and systemic lupus erythematosus, chronic idiopathicurticarias and heme malignancies. Dosage forms adapted for topicaladministration to the skin are commonly used for treating atopicdermatitis, psoriasis and chronic and acute urticaria conditions, andautoimmune bullous conditions including pemphigus and pemphigoid. Dosageforms adapted for inhalation or oral administration are commonly usedfor treating COPD; whilst dosage forms adapted for intranasaladministration are commonly used for treating allergic rhinitis.

Suitable pharmaceutically acceptable excipients will vary depending uponthe particular dosage form chosen. In addition, suitablepharmaceutically acceptable excipients may be chosen for a particularfunction that they may serve in the composition. For example, certainpharmaceutically acceptable excipients may be chosen for their abilityto facilitate the production of uniform dosage forms. Certainpharmaceutically acceptable excipients may be chosen for their abilityto facilitate the production of stable dosage forms. Certainpharmaceutically acceptable excipients may be chosen for their abilityto facilitate the carrying or transporting the compound of formula (I)once administered to the patient from one organ, or portion of the body,to another organ, or portion of the body. Certain pharmaceuticallyacceptable excipients may be chosen for their ability to enhance patientcompliance.

Suitable pharmaceutically acceptable excipients include the followingtypes of excipients: diluents, fillers, binders, disintegrants,lubricants, glidants, granulating agents, coating agents, wettingagents, solvents, co-solvents, suspending agents, emulsifiers,sweetners, flavouring agents, flavour masking agents, colouring agents,anticaking agents, humectants, chelating agents, plasticizers, viscosityincreasing agents, antioxidants, preservatives, stabilizers,surfactants, and buffering agents. The skilled artisan will appreciatethat certain pharmaceutically acceptable excipients may serve more thanone function and may serve alternative functions depending on how muchof the excipient is present in the formulation and what otheringredients are present in the formulation.

Skilled artisans possess the knowledge and skill in the art to enablethem to select suitable pharmaceutically acceptable excipients inappropriate amounts for use in the invention. In addition, there are anumber of resources that are available to the skilled artisan whichdescribe pharmaceutically acceptable excipients and may be useful inselecting suitable pharmaceutically acceptable excipients. Examplesinclude Remington's Pharmaceutical Sciences (Mack Publishing Company),Remington: The Science and Practice of Pharmacy, (Lippincott Williams &Wilkins), The Handbook of Pharmaceutical Additives (Gower PublishingLimited), and The Handbook of Pharmaceutical Excipients (the AmericanPharmaceutical Association and the Pharmaceutical Press).

The pharmaceutical compositions of compounds of formula (I) are preparedusing techniques and methods known to those skilled in the art. Some ofthe methods commonly used in the art are described in Remington'sPharmaceutical Sciences (Mack Publishing Company).

Oral solid dosage forms such as tablets will typically comprise one ormore pharmaceutically acceptable excipients, which may for example helpimpart satisfactory processing and compression characteristics, orprovide additional desirable physical characteristics to the tablet.Such pharmaceutically acceptable excipients may be selected fromdiluents, binders, glidants, lubricants, disintegrants, colorants,flavourants, sweetening agents, polymers, waxes or othersolubility-modulating materials.

Dosage forms for topical administration to the skin may, for example, bein the form of ointments, creams, lotions, eye ointments, eye drops, eardrops, impregnated dressings, and aerosols, and may contain appropriateconventional additives, including, for example, preservatives, solventsto assist drug penetration, and emollients in ointments and creams. Suchtopical formulations may also contain compatible conventional carriers,for example cream or ointment bases, and ethanol or oleyl alcohol forlotions. Such carriers may constitute from about 1% to about 98% byweight of the formulation; more usually they will constitute up to about80% by weight of the formulation.

Dosage forms for parenteral administration will generally comprisefluids, particularly intravenous fluids, i.e., sterile solutions ofsimple chemicals such as sugars, amino acids or electrolytes, which canbe easily carried by the circulatory system and assimilated. Such fluidsare typically prepared with water for injection USP. Fluids usedcommonly for intravenous (IV) use are disclosed in Remington, TheScience and Practice of Pharmacy [ibid]. The pH of such IV fluids mayvary, and will typically be from 3.5 to 8, as known in the art.

Dosage forms for nasal or inhaled administration may conveniently beformulated as aerosols, solutions, drops, gels or dry powders.

Dosage forms for topical administration to the nasal cavity (nasaladministration) include pressurised aerosol formulations and aqueousformulations administered to the nose by pressurised pump. Formulationswhich are non-pressurised and adapted for nasal administration are ofparticular interest. Suitable formulations contain water as the diluentor carrier for this purpose. Aqueous formulations for administration tothe nose may be provided with conventional excipients such as bufferingagents, tonicity modifying agents and the like. Aqueous formulations mayalso be administered to the nose by nebulisation.

Dosage forms for nasal administration are provided in a metered dosedevice. The dosage form may be provided as a fluid formulation fordelivery from a fluid dispenser having a dispensing nozzle or dispensingorifice through which a metered dose of the fluid formulation isdispensed upon the application of a user-applied force to a pumpmechanism of the fluid dispenser. Such fluid dispensers are generallyprovided with a reservoir of multiple metered doses of the fluidformulation, the doses being dispensable upon sequential pumpactuations. The dispensing nozzle or orifice may be configured forinsertion into the nostrils of the user for spray dispensing of thefluid formulation into the nasal cavity. In one embodiment, the fluiddispenser is of the general type described and illustrated inWO2005/044354A1. The dispenser has a housing which houses a fluiddischarge device having a compression pump mounted on a container forcontaining a fluid formulation. The housing has at least onefinger-operable side lever which is movable inwardly with respect to thehousing to cam the container upwardly in the housing to cause the pumpto compress and pump a metered dose of the formulation out of a pumpstem through a nasal nozzle of the housing. A particularly preferredfluid dispenser is of the general type illustrated in FIGS. 30-40 ofWO2005/044354A1.

Aerosol compositions, e.g. for inhaled administration, can comprise asolution or fine suspension of the active substance in apharmaceutically acceptable aqueous or non-aqueous solvent. Aerosolformulations can be presented in single or multidose quantities insterile form in a sealed container, which can take the form of acartridge or refill for use with an atomising device or inhaler.Alternatively the sealed container may be a unitary dispensing devicesuch as a single dose nasal inhaler or an aerosol dispenser fitted witha metering valve (metered dose inhaler) which is intended for disposalonce the contents of the container have been exhausted.

Where the dosage form comprises an aerosol dispenser, it preferablycontains a suitable propellant under pressure such as compressed air,carbon dioxide or an organic propellant such as a hydrofluorocarbon(HFC). Suitable HFC propellants include 1,1,1,2,3,3,3-heptafluoropropaneand 1,1,1,2-tetrafluoroethane. The aerosol dosage forms can also takethe form of a pump-atomiser. The pressurised aerosol may contain asolution or a suspension of the active compound. This may require theincorporation of additional excipients e.g. co-solvents and/orsurfactants to improve the dispersion characteristics and homogeneity ofsuspension formulations. Solution formulations may also require theaddition of co-solvents such as ethanol. Other excipient modifiers mayalso be incorporated to improve, for example, the stability and/or tasteand/or fine particle mass characteristics (amount and/or profile) of theformulation.

For pharmaceutical compositions suitable and/or adapted for inhaledadministration, it is preferred that the pharmaceutical composition is adry powder inhalable composition. Such a composition can comprise apowder base such as lactose, glucose, trehalose, mannitol or starch, acompound of formula (I) (preferably in particle-size-reduced form, e.g.in micronised form), and optionally a performance modifier such asL-leucine or another amino acid, cellobiose octaacetate and/or metalssalts of stearic acid such as magnesium or calcium stearate. Preferably,the dry powder inhalable composition comprises a dry powder blend oflactose and a compound of formula (I). The lactose is preferably lactosehydrate e.g. lactose monohydrate and/or is preferably inhalation-gradeand/or fine-grade lactose. Preferably, the particle size of the lactoseis defined by 90% or more (by weight or by volume) of the lactoseparticles being less than 1000 microns (micrometres) (e.g. 10-1000microns e.g. 30-1000 microns) in diameter, and/or 50% or more of thelactose particles being less than 500 microns (e.g. 10-500 microns) indiameter. More preferably, the particle size of the lactose is definedby 90% or more of the lactose particles being less than 300 microns(e.g. 10-300 microns e.g. 50-300 microns) in diameter, and/or 50% ormore of the lactose particles being less than 100 microns in diameter.Optionally, the particle size of the lactose is defined by 90% or moreof the lactose particles being less than 100-200 microns in diameter,and/or 50% or more of the lactose particles being less than 40-70microns in diameter. Most importantly, it is preferable that about 3 toabout 30% (e.g. about 10%) (by weight or by volume) of the particles areless than 50 microns or less than 20 microns in diameter. For example,without limitation, a suitable inhalation-grade lactose is E9334 lactose(10% fines) (Borculo Domo Ingredients, Hanzeplein 25, 8017 J D Zwolle,Netherlands).

Optionally, in particular for dry powder inhalable compositions, apharmaceutical composition for inhaled administration can beincorporated into a plurality of sealed dose containers (e.g. containingthe dry powder composition) mounted longitudinally in a strip or ribboninside a suitable inhalation device. The container is rupturable orpeel-openable on demand and the dose of e.g. the dry powder compositioncan be administered by inhalation via the device such as the DISKUS®device, marketed by GlaxoSmithKline. The DISKUS® inhalation device isfor example described in GB 2242134 A, and in such a device at least onecontainer for the pharmaceutical composition in powder form (thecontainer or containers preferably being a plurality of sealed dosecontainers mounted longitudinally in a strip or ribbon) is definedbetween two members peelably secured to one another; the devicecomprises: a means of defining an opening station for the said containeror containers; a means for peeling the members apart at the openingstation to open the container; and an outlet, communicating with theopened container, through which a user can inhale the pharmaceuticalcomposition in powder form from the opened container.

A composition of invention compound of formula (I), for intranasaladministration, may also be adapted for dosing by insufflation, as a drypowder formulation.

For dosage forms for inhaled administration, where the compound offormula (I) is present as a dry powder or in suspension, then it ispreferred that it is in a particle-size-reduced form. Preferably thesize-reduced form is obtained or obtainable by micronisation. Thepreferable particle size of the size-reduced (e.g. micronised) compoundor salt is defined by a D50 value of about 0.5 to about 10 microns (forexample as measured using laser diffraction).

It will be appreciated that when the compounds of formula (I) areadministered in combination with other therapeutic agents normallyadministered by the inhaled, intravenous, oral, topical or intranasalroute, that the resultant pharmaceutical composition may be administeredby the same routes.

The composition may contain from 0.1% to 100% by weight, for examplefrom 10 to 60% by weight, of the active material, depending on themethod of administration. The composition may contain from 0% to 99% byweight, for example 40% to 90% by weight, of the carrier, depending onthe method of administration.The compounds of the formula (I) mayconveniently be administered in amounts of, for example, 1 μg to 2 g.The precise dose will of course depend on the age and condition of thepatient and the particular route of administration chosen.

Biological Test Methods

Compounds may be tested for in vitro activity in accordance with thefollowing assays:

1. Basic SYK Enzyme Activity

3 μl of SYK lysate diluted 16-fold in assay buffer (20 mM TRIS pH 7.4,0.01% BSA,0.1% Pluronic F-68) was added to wells containing 0.1 μl ofvarious concentrations of compound or DMSO vehicle (1.7% final) in aGreiner low volume 384 well black plate. Following 15 minutespre-incubation at room temperature, the reaction was initiated by theaddition of 3 μl of substrate reagent containing Y7 Sox peptide,(Invitrogen Cat. #KNZ3071, 5 μM final), ATP (35 μM final) and MgCl₂ (10mM final) in assay buffer. The reaction was incubated at roomtemperature before measuring fluorescence intensity (λ_(ex) 360/λ_(em)485) on an Envision plate reader (Perkin Elmer Life Sciences, Waltham,Mass., USA) at 15 minutes and 55 minutes post-substrate addition.

The compounds of the Examples were tested essentially as describedabove, and were found to have a pIC₅₀ of 5.5 to 7.5. The compounds ofExamples 1 to 8 were tested essentially as described above and werefound to have an average pIC₅₀ value in this assay of 6.0. The compoundof Example 2 was tested essentially as described above and was found tohave a pIC₅₀ of 7.1.

Those of skill in the art will recognize that in vitro binding assaysand cell-based assays for functional activity are subject tovariability. Accordingly, it is to be understood that the values for thepIC₅₀s recited above are exemplary only.

Preparation of SYK Lysate

i. Preparation of Ramos Cell Lysates

Ramos B Cells (human B cells of Burkitt's lymphoma, clone 296.4C10,ATCC) were cultured in suspension in growth medium (RPM1-1640, Sigma;supplemented with 2 mM L-glutamine, Gibco; 10 mM Hepes, Sigma; 1 mMsodium pyruvate, Sigma; 10% v/v heat-inactivated FCS, Gibco). Cells weregrown in Corning Cellstacks (6360 cm²) in 1 litre volume and viabilityand cell density were monitored daily. Cells were maintained at<1.5×10e6/ml and >92% viability

Large scale production runs were generated from Large Scale IntermediateAliquots (LSIA's) of frozen Ramos cells as this was found to givegreater reproducibility than production from a continuously growingculture of Ramos cells.

The large scale production run cells were generated in four steps:

1. Thaw LSIA into 1 × Cellstack;

2. Expand culture into 4 × Cellstack;

3. Expand from 4 to 12 × Cellstacks;

4. Harvest all 12 Cellstacks

Cellstacks were harvested in 2L centrifuge bottles using a SorvallMistral centrifuge, 2000 rpm, 10 minutes, 4° C. (2L×2×10⁶ cells/ml=4×10⁹cells total)

(Notes for cell scale-up: If the cell density exceeded 1.8×10e6/ml orviability dropped below 90% the Syk prep obtained post-stimulation waslikely to be of lower activity).

Also, repeated passage of the Ramos cells seemed to have a detrimentaleffect on Syk activity when cell growth is done at scale (this did notseem to be the case in small scale cultures)—it is recommended always touse LSIA's and modular scale-up for large scale preps.

ii. Stimulation of Ramos Cells with Anti-IgM Ab to Produce Syk &Preparation of Lysates

Cells were stimulated at 20×10⁶ cells/ml using 15 ug/ml (finalconcentration) anti-IgM antibody. Following harvest (as describedabove), a total of 4×10⁹ cells were resuspended in 180 mls pre-warmed(37° C.) DPBS in a Corning 500 ml centrifuge bottle. 20 mls anti-IgMantibody at 150 ug/ml were added to each 500 ml centrifuge bottle.(working stock made up in DPBS pre-warmed to 37° C.). Cells wereincubated for exactly 5 minutes at 37° C. following the addition of antiIgM antibody. Following 5 minutes stimulation, 300 mls ice-cold DPBSwere added to each bottle to stop the stimulation (temperature drops to˜12 deg C) then cells were centrifuged at 2000 rpm (Sorvall Legend RT+centrifuge—pre-chilled to 4 deg C). Cells were washed by resuspension inice-cold DPBS and centrifugation as above. The cell pellet was thenlysed in ice-cold lysis buffer containing 1% triton-x-100 at a ratio of150 ul/1×10⁷ cells (i.e. 48 mls lysis buffer). Following the addition oflysis buffer, the cells were pipetted up & down & kept on ice for 15minutes. The clarified lysate was then obtained by centrifugation(Sorvall Evolution RC (SLA-1500 rotor, ˜20,000 g (˜14,500rpm), 45 min,4° C.).

Lysate was aliquoted, snap-frozen on dry-ice & stored at −80° C. priorto assay.

Materials

Ramos Cells: Human B cells of Burkitts lymphoma, clone 296.4C10 (ATCC).Growth Media: 500 ml RPMI, 10% heat inactivated FCS, 2 mM L-Glutamine, 2mM HEPES, 1 mM sodium pyruvate.

RPMI: Sigma R0883, stores CT5652

Foetal Calf Serum: Gibco 10099-141, stores CT2509

L-Glutamine: 200 mM, Gibco 25030, stores CT3005

HEPES: 1M, Sigma H0887, stores CT5637

Sodium Pyruvate: 100 mM, Sigma S8636, stores CT7741

Anti-IgM Ab: Goat anti-human IgM ((Fab′)2 fragments) in PBS. Invitrogen,custom-made preparation (azide free and low endotoxin levels). Catalogueno. NON0687, Lot 1411913.2.74 mg/ml.

D-PBS: Dulbeccos phosphate buffered saline, Sigma D8537

Lysis Buffer: 50 mM TRIS pH7.5+150 mM NaCl+1% Triton-X-100+2 mMEGTA+1:100 dilution inhibitor cocktails (Phosphatase inhibitor cocktailset II, Calbiochem cat no. 524625 & Protease inhibitor cocktail set V,Calbiochem cat no. 539137) Triton-X-100: Roche 10 789 704 001 (GI198233X, SC/159824). Made up as a 20% stock in water.

EGTA: Sigma E4378. Added solid directly to buffer.

2. B Cell Activity Assays

2.1. Ramos pErk Assay

Principle of the Assay

Ramos B cells (human B cells of Burkitt's Lymphoma) are stimulated usinganti-IgM. This results in the recruitment of SYK to the B cell receptor.The subsequent autophosphorylation of Syk leads to initiation of asignalling cascade resulting in B cell activation via the Erk MAP Kinasepathway. As a result Erk is phosphorylated and following cell lysis isdetected by an immune capture assay.

Stimulation of Ramos Cells with Anti-IgM

Cells were plated at a density of 2.5×10⁵/well in a volume of 25 μlassay medium (RPMI containing 10% heat inactivated foetal calf serum, 1%L-glutamine) in 96 v-well polypropylene plates. 25 μl appropriatelydiluted compound solution was added and the plate incubated for 30 minat 37° C. with 5% CO₂. Cells were stimulated with 5 μl Fab′₂ fragmentsof goat anti-human IgM (5 μg/ml final) for 7 min at 37° C. Cells arelysed by the addition of 55 μL 2× RIPA lysis buffer for 2 h at 4° C.Lysate may be frozen at this point at −80° C.

pErk MSD Assay

50 μl cell lysate was transferred to a 96 well MSD plate coated withanti-pErk1/2 (Thr/Tyr: 202/204; 185/187) capture antibody and incubatedfor 16 hours at 4° C. or 3 hours at room temperature. The plate waswashed and an anti-pErk detection antibody added (25 μl/well) for 1 hourat room temperature. This was removed, 150 μL MSD read buffer added andthe resultant electrochemiluminescence signal measured.

Compound Preparation

Compound was prepared as a 10 mM stock in DMSO and a dilution seriesprepared in DMSO using 9 successive 5-fold dilutions. This dilutionseries was diluted a further 1:100 with assay medium to give the finalconcentration range to be tested of 5×10⁻⁵ to 2.56×10⁻¹¹M. Compounddilutions were prepared using the Biomek 2000 and Biomek Nx automatedrobotic pipetting systems.

Compounds of Examples 1-4, 6, 7, 9, 10-12, 15-17, 19, 20, 22, 24, 26-39,41, 45, 46, 48 and 49 were tested essentially as described above, andwere found to have average pIC₅₀ values of 5.2 to 6.8. The compounds ofExamples 1, 2, 3 and 4 were tested essentially as described above andwere found to have an average pIC₅₀ value in this assay of ≧6.0.

Those of skill in the art will recognize that in vitro binding assaysand cell-based assays for functional activity are subject tovariability. Accordingly, it is to be understood that the values for thepIC₅₀s recited above are exemplary only.

INTERMEDIATES AND EXAMPLES

General

All temperatures are in ° C.

BOC refers to tert-butoxycarbonyl

BOC₂O refers to Di-tert-butyl dicarbonate

BuOH refers to butanol

Cs₂CO₃ refers to caesium carbonate

DCM/CH₂Cl₂ refers to dichloromethane

DEAD refers to diethyl azodicarboxylate

Dioxane refers to 1,4-dioxane

DIPEA refers to N, N-diisopropylethylamine

DMSO refers to dimethylsulfoxide

DME refers to 1, 2-dimethoxyethane

DMF refers to N,N-dimethylformamide

Dppf refers to 1,1′-Bis(diphenylphosphino)ferrocene

EA refers to ethyl acetate

EDC refers to N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide

Et₃N refers to triethylamine

Ether refers to diethyl ether

EA/EtOAc refers to ethyl acetate

h refers to hours

HCl refers to hydrogen chloride

HOBT refers to 1-hydroxybenzotriazole

HPLC refers to high performance liquid chromatography

K₂CO₃ refers to potassium carbonate

KOH refers to potassium hydroxide

LCMS refers to liquid chromatography-mass spectroscopy

MDAP refers to mass directed automated preparative chromatography

min refers to minutes

NaHCO₃ refers to sodium bicarbonate

NH₄Cl refers to ammonium chloride

NMP refers to N-methylpyrrolidone

PEPPSI refers to Pyridine-Enhanced Precatalyst Preparation Stabilizationand

Initiation

Pd/C refers to palladium on carbon

PdCl₂.dppf refers to[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium

Pd(PPh₃)₄ or Tetrakis refers to tetrakis (triphenylphosphine) palladium(0)

Pinacol diborane refers to4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane

r.t. refers to room temperature

Rt refers to retention time

SiO₂ refers to silicon dioxide

TEA refers to triethylamine

Tf refers to trifluoromethanesulfonyl

TFA refers to trifluoroacetic acid

THF refers to tetrahydrofuran

TLC/tlc refers to thin layer chromatography

¹H NMR spectra were recorded using a Bruker DPX 400 MHz, referenced totetramethylsilane.

Mass spectra were recorded on a SHIMADZU LCMS 2010 EV Spectrometer usingPositive/negative electrospray. Sample preparation was done in 100%methanol and the samples were injected via direct injection port

Silica chromatography techniques include either automated (Flashmaster,Biotage SP4) techniques or manual chromatography on pre-packedcartridges (SPE) or manually-packed flash columns.

When the name of a commercial supplier is given after the name of acompound or a reagent, for instance “compound X (Aldrich)” or “compoundX/Aldrich”, this means that compound X is obtainable from a commercialsupplier, such as the commercial supplier named.

Similarly, when a literature or a patent reference is given after thename of a compound, for instance compound Y (EP 0 123 456), this meansthat the compound may be prepared as described in the named reference.

The names of the above mentioned Examples have been obtained using thecompound naming programme “ACD Name Pro 6.02”.

General HPLC Method

HPLC was carried out using X-Bridge C18 250×4.6 mm, 5 micron at 267 nm.Column flow was 1 mL/min and solvents used were 0.1% TFA in water HPLCgrade (A) and 0.1% TFA in MeCN Gradient grade (B), with an injectionvolume of 10 μL. Sample preparation in 250 ppm in Water: MeCN.

Method is as described below.

Time (min) A B % 0.01 90 10 9.00 10 90 11.00 0 100 20.00 0 100 20.01 9010 25.00 90 10

General LC-MS Methods

Method-A

LC-MS was carried out using X-bridge C18 150×4.6 mm, 5 micron column.The UV detection was done at wavelength of maximum absorption (mentionedon individual spectra). The mass spectra were recorded on a SHIMADZULCMS 2010EV Spectrometer using Positive/negative electro spray. Columnflow was 1 mL/min and solvents used were 0.1% formic acid in HPLC gradewater (A) and 0.1% formic acid in MeCN HPLC grade (B), with an injectionvolume of 10 μL. Sample preparation was at 250 ppm in MeCN+water.

Method is as described below.

Time (min) A B % 0.01 90 10 5.00 10 90 6.00 0 100 10.00 0 100 10.01 9010 12.00 90 10

Method-B

LC-MS was carried out using X-bridge C18 150×4.6 mm, 5 micron column.The UV detection was done at wavelength of maximum absorption (mentionedon individual spectra). The mass spectra were recorded on a SHIMADZULCMS 2010 EV Spectrometer using Positive/negative electro spray. Columnflow was 1 mL/min and solvents used were 0.05% Ammonium Acetate in HPLCgrade water (A) and 0.05% Ammonium acetate in Methanol HPLC grade (B),with an injection volume of 10 μL. Sample preparation was at 250 ppm inMeOH+water.

Method is as described below.

Time (min) A B % 0.01 90 10 5.00 10 90 6.00 0 100 10.00 0 100 10.01 9010 12.00 90 10

Method C

LC/MS (Aglient) was conducted on a HALO C18 column (50 mm×4.6 mm i.d.2.7 μm packing diameter) at 40 degrees centigrade, eluting with 0.1% v/vsolution of Formic Acid in Water (Solvent A) and 0.1% v/v solution ofFormic Acid in Acetonitrile (Solvent B) using the following elutiongradient 0-1 min 5% B, 1-2.01 min 95% B, 2.01-2.5 min 5% B at a flowrate of 1.8 ml/min. The UV detection was a summed signal at wavelength:214 nm and 254 nm. MS: Ion Source: ESI; Drying Gas Flow: 10 L/min;Nebulizer Pressure: 45 psi; Drying Gas Temperature: 330° C.; CapillaryVolvage: 4000 V.

Preparative HPLC Method Used for the Purification of Compound Example 5

Preparative HPLC was carried out on Waters Delta 600 using Gemini C18150×21.2 mm, 5 micron column with the UV detection at 251 nm on a UVdetector. Column flow was 21 mL/min. and solvents used were 0.1% TFA inwater HPLC grade (A) and 0.1% TFA in Acetonitrile HPLC grade (B). Samplewas prepared in 1:1 Water & Acetonitrile.

Method is as described below.

Time (min) B % 0.01 25 5.5 55 5.51 100 9.0 100 9.01 25 11 25

Preparative HPLC Method Used for the Purification of Compound Example 6

Preparative HPLC was carried out using ACE C₁₈ 250×21.2 mm, 5 microncolumn with the UV detection at 249 nm on a PDA detector. Column flowwas 21 mL/min. and solvents used were 0.1% TFA in water HPLC grade (A)and 0.1% TFA in MeCN Gradient grade (B). Sample was prepared in amixture of water and acetonitrile.

Method is as described below.

Time (min) B % 0.01 30 7.00 50 8.00 100 12.00 100 12.01 30 14.00 30

Other compounds purified by preparative HPLC were purified by methodssimilar to those described above for examples 5 and 6

Intermediate 1: 1,1-dimethylethyl7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate

To a degassed mixture of 1,1-dimethylethyl7-{[(trifluoromethyl)sulfonyl]oxy}-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate(9.9 g) (which can be prepared according to J. Med Chem. 2007, 50(21)5076-5089), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane(7.6 g), potassium acetate (7.3 g) and dppf (0.833 g) in dioxane (165ml) was added PdCl₂dppf.CH₂Cl₂ (1.2 g). The reaction mixture was againdegassed with nitrogen/vacuum cycles. This was heated at 100° C. for 18h. It was diluted with ethyl acetate and filtered through celite. Thefiltrate was concentrated to yield a crude product. This was purified bycolumn chromatography eluting with a 0-6% gradient of ethyl acetate inhexane to give the title compound as a white solid (6.2 g)

LCMS (Method B): Rt=8.00 min, [MH]+-100=274 (loss of BOC group asartefact of the mass spectroscopy conditions)

Intermediate 18, 2-bromo-6-methyl-3-pyridinol

To a solution of 5-hydroxy-2-methlypyridine (Commercial, Aldrich, 44.5g) in pyridine (400 ml) is added dropwise over 30 min at roomtemperature a solution of bromine (71.64 g) in pyridine (550 ml). Thereaction mixture was stirred for an additional 1.5 h. The reactionmixture was poured into water (4 litres), stirred for a few minutes andextracted with diethyl ether (4×300 ml). The combined organics weredried over sodium sulphate and concentrated in vacuo to give a brownsolid that was purified through silica using a 0-30% ethyl acetate inhexane system, to give the title compound as a beige solid, 37 g.

NMR ¹H NMR (400 MHz, DMSO-d6) δ ppm 10.43 (1H, s, OH), 7.16 ppm (1H, d,CH), 7.06 (1H, d, CH), 2.31 (3H, s, CH3)

Intermediate 19, (4-ethyl-2-pyridinyl)methanol

A solution of 4-ethylpyridine (Commercial, e.g. Sigma-Aldrich) (10.7 g),ammonium peroxydisulfate (45.6 g) and concentrated sulphuric acid (4.5ml) in methanol (150 ml)/water (70 ml) was refluxed for 24 h. Thereaction mixture was slowly added onto aqueous sodium bicarbonate andextracted with chloroform (4×500 ml). This was dried over sodiumsulphate, concentrated in vacuo and purified through silica using 0-60%ethyl acetate in hexane to give the title compound, 1.16 g

Mass Spec: [MH]+=138.0

Intermediate 20, 2-bromo-4-(ethyloxy)phenol

To a solution of 4-(ethyloxy)phenol (Commercial eg Aldrich) (1.0 g) inchloroform (5 ml) cooled to 0° C. was added bromine (1.26 g) dropwiseover 20 min. The resulting mixture was stirred at 25C for 2 h, beforewashing sequentially with aqueous sodium bicarbonate, and brine. Theorganics were dried over sodium sulphate, filtered and concentrated invacuo to yield the title compound, 1.8 g

LCMS (Method A): Rt=6.52 min, [MH]+=215, 217

Intermediate 65, 3-bromo-4-hydroxy-N-methylbenzamide

To a stirred solution of 3-bromo-4-hydroxybenzoic acid (Commercial egAldrich) (2.0 g), EDC (2.65 g), HOBT (1.41 g) and TEA (6.2 ml) in DCM(60 ml) was added methylamine hydrochloride (1.87 g). This was stirredat 25-30C for 16 h. The solvent was removed under reduced pressure. Theresidue was dissolved in water and extracted with ethyl acetate. Theorganics were dried (sodium sulphate) and concentrated in vacuo to yieldthe title compound, 0.57 g

LCMS (Method B): Rt=4.76 min

Prepared similarly using a different amine was intermediate 66.

Intermediate Amine Amount Characterisation 66 Dimethylamine, 0.52 g LCMS3-bromo-4-hydroxy- hydrochloride (Method B): N,N- Rt = 5.21 min,dimethylbenzamide [MH]+ = 244, 266

Intermediate 67, 3-bromo-4-hydroxybenzamide

To a stirred solution of 3-bromo-4-hydroxybenzoic acid (0.5 g) and DMF(0.1 ml) in DCM (10 ml) was added dropwise oxalyl chloride (0.6 ml).After stirring for 2 h, ammonia gas was purged through. After completionof reaction by tic, the solvent was removed under reduced pressure. Theresidue was dissolved in water and extracted with ethyl acetate. Theorganics were dried over sodium sulphate and concentrated in vacuo toyield the title compound, 0.18 g

LCMS (Method A): Rt=4.33 min, [MH]⁺=216, 218

Intermediate 68 1,2-bis(methyloxy)-4-{[(methyloxy)methyl]oxy}benzene

To a stirred solution of 3,4-bis(methyloxy)phenol (Commercial eg AlfaAesar) (1.0 g) and DIPEA (2.28 ml) in DCM (15 ml) was added chloromethylmethyl ether (0.74 ml) at 0C. After stirring at 25-30C for 17 h, thereaction was washed with dilute hydrochloric acid and saturated aqueoussodium bicarbonate. This was dried over sodium sulphate and purifiedthrough silica eluting with 0-5% ethyl acetate in hexane, to give thetitle compound, 0.80 g

LCMS (Method A): Rt=5.99 min, [MH]⁺=199

Intermediate 692-bromo-3,4-bis(methyloxy)-1-{[(methyloxy)methyl]oxy}benzene

To a stirred solution of1,2-bis(methyloxy)-4-{[(methyloxy)methyl]oxy}benzene (4.0 g) and TMEDA(3.93 ml) in dry diethyl ether (50 ml) was added tert-butyllithium (1.7Min pentane, 23.76 ml) at -70C. The reaction was stirred at thistemperature for 1 h before adding bromine (0.15 ml). This was allowed tostir at 0C for 3 h. The reaction was quenched by addition of 20% aqueoussodium dithionite and extracted with ethyl acetate. The organics werewashed with dilute hydrochloric acid, aqueous sodium bicarbonate, brineand dried over sodium sulphate to yield a crude product. This waspurified through silica, eluting with 0-10% ethyl acetate in hexane togive the title compound, 1.4 g

Mass Spec: [MH]+=277, 279

Intermediate 70, 2-bromo-3,4-bis(methyloxy)phenol

To a stirred solution of2-bromo-3,4-bis(methyloxy)-1-{[(methyloxy)methyl]oxy}benzenein methanol(10 ml) was added hydrochloric acid (12M, 0.12 ml) at 25C. The reactionmixture was stirred at 40C for 5 h. The reaction mixture was partitionedbetween ethyl acetate and saturated aqueous sodium bicarbonate. Theorganics were washed with brine, dried over sodium sulphate andconcentrated in vacuo. The crude product was purified through silicaeluting with 0-4% ethyl acetate in hexane, to give the title compound,0.65 g

LCMS (Method B): Rt=5.58 min, [MH]⁺=233

Intermediate 2: 2-bromo-3-{[(4-methyl-2-pyridinyl)methyl]oxy}pyridine

A mixture of 2-bromo-3-pyridinol (commercially available, e.g. fromAldrich) (2.9 g) and potassium carbonate (6.94 g) in DMF (25 ml) wasstirred for 20 min before adding 2-(chloromethyl)-4-methyl pyridinehydrochloride (for preparation see WO 2008/141011) (3 g). This wasstirred at room temperature overnight. The reaction mixture was pouredinto ice/water and the solid formed was collected by filtration, washedwith hexane and dried to give the title compound, 2.87 g (61%).

LCMS (Method A): Rt=4.27 min, [MH]+=279, 281.

The following intermediates were similarly prepared:

Intermediate Alkylating agent Phenol Amount Characterisation 32-({[2-bromo-3- (methyloxy)phenyl]oxy} methyl)-4- methylpyridine2-(chloromethyl)- 4-methylpyridine, hydrochloride

 1.9 g (39%) LCMS (Method A): Rt = 5.16 min, [MH]+ = 308, 310Preparation: J. Organic Chem. 2003, 68 (4) 1401-1408 4 2-({[2-bromo-5-(methyloxy)phenyl]oxy} methyl)-4- methylpyridine 2- (chloromethyl)- 4-methylpyridine, hydrochloride

  3 g (59%) LCMS (Method A): Rt = 5.71 min, [MH]+ = 308, 310Preparation: Synthetic Communications, 2007, 37 (2) 323-328 51-(3-bromo-4-{[(4- methyl-2- pyridinyl)methyl]oxy} phenyl)ethanone 2-(chloromethyl)- 4- methylpyridine, hydrochloride

 2.6 g (49%) LCMS (Method A): Rt = 5.29 min, [MH]+ = 320, 322Preparation: WO 2010/102154 6 2-{[(2-bromo-4- fluorophenyl)oxy] methyl}-4-methylpyridine 2- (chloromethyl)- 4- methylpyridine, hydrochloride

 1.3 g (81%) LCMS (Method B): Rt = 7.39 min, [MH]+ = 296, 298 Commercial(Aldrich) 7 1-{3-bromo-4-[(2- pyrazinylmethyl)oxy] phenyl}ethanone 2-(chloromethyl) pyrazine (Preparation WO 2010/132615

*3.1 g (35%) LCMS (Method B): Rt = 5.29 min, [MH]+ = 307, 309Preparation: WO 2010/102154 8 2-{[(2- bromophenyl)oxy] methyl}-4-(methyloxy)pyridine 2-(chloromethyl)- 4-(methyloxy) pyridine,hydrochloride Commercial eg ABCR GmbH

 3.0 g *(99%) LCMS (Method A): Rt = 4.53 min, [MH]+ = 294, 296Commercial eg Aldrich 9 1-{3-bromo-4-[(2- pyridinylmethyl)oxy]phenyl}ethanone 2- (Bromomethyl) pyridine hydrobromide Commercial(Aldrich)

#11.6 g  (74%) HPLC: Rt = 10.31 min. Mass Spec: [MH]+ = 305.9Preparation: WO 2010/102154 21 2-bromo-6-(1,1- dimethylethyl)-3-{[(4-methyl-2- pyridinyl)methyl]oxy} pyridine 2- (chloromethyl)- 4-methylpyridine, hydrochloride

0.23 g Mass Spec: [MH]+ = 334.9 Preparation: Intermediate 63 222-({[2-bromo-4- (methyloxy)phenyl]oxy} methyl)pyridine 2- (Bromomethyl)pyridine hydrobromide Commercial (Aldrich)

#10.38 g  LCMS (Method A): Rt = 7.86 min. [MH]+ = 294, 296 Commercial egTCI (Europe) 23 2-{[(2-bromo-6-methyl- 3- pyridinyl)oxy]methyl} pyrazine2- (chloromethyl) pyrazine

*1.19 g  HPLC: Rt = 8.66 min. Preparation: Intermediate 18 242-({[2-bromo-4- (methyloxy)phenyl]oxy} methyl)pyrazine 2- (chloromethyl)pyrazine

*2.3 g HPLC: Rt = 9.54 min. Commercial eg Apollo Scientific Ltd. 252-bromo-6-methyl-3- {[(4-methyl-2- pyridinyl)methyl]oxy} pyridine 2-(chloromethyl)- 4- methylpyridine, hydrochloride

11.3 g Mass Spec: [MH]+ = 292.9, 295 LCMS (Method): Rt = 6.53 min. [MH]+= 293, 295 26 2-({2-bromo-4- (methyloxy)phenyl]oxy} methyl)-4-(methyloxy)pyridine 2- (chloromethyl)- 4-(methyloxy) pyridine Commercialeg ChemBridge

0.886 g  Mass Spec: [MH]+ = 323.9 27 2-({[2-bromo-4-(methyloxy)phenyl]oxy} methyl)-4- methylpyridine 2- (chloromethyl)- 4-methylpyridine, hydrochloride

0.68 g Mass Spec: [MH]+ = 307.9 28 1-[3-bromo-4-({[4- (methyloxy)-2-pyridinyl]methyl}oxy) phenyl]ethanone 2- (chloromethyl)- 4- (methyloxy)pyridine

#0.35 g  Mass Spec: [MH]+ = 335.9 29 2-{[(2-bromo-4- methylphenyl)oxy]methyl}-4- methylpyridine 2- (chloromethyl)- 4- methylpyridine,hydrochloride

 1.0 g LCMS (Method B): Rt = 7.64 min, [MH]+ = 292, 294 Commercial e.g.Aldrich 30 2-({[2-bromo-4- (ethyloxy)phenyl]oxy} methyl)-4-methylpyridine 2- (chloromethyl)- 4- methylpyridine, hydrochloride

 1.1 g LCMS (Method A): Rt = 7.59 min, [MH]+ = 322, 324 Preparation:WO2008079610 31 2-({[2-bromo-4- (trifluoromethyl)phenyl] oxy}methyl)-4-methylpyridine 2- (chloromethyl)- 4- methylpyridine, hydrochloride

 1.3 g LCMS (Method B): Rt = 7.64 min, [MH]+ = 346, 348 Commercial egFluorochem 32 3-bromo-4-{[(4-methyl- 2- pyridinyl)methyl]oxy}benzonitrile 2- (chloromethyl)- 4- methylpyridine, hydrochloride

 1.1 g LCMS (Method B): Rt = 6.95 min, [MH]+ = 303, 305 Commercial egAldrich 33 2-({[2-bromo-4-(1,1- dimethylethyl)phenyl]oxy} methyl)-4-methylpyridine 2- (chloromethyl)- 4- methylpyridine, hydrochloride

0.77 g Mass Spec: [MH]+ = 333.9 Commercial eg Apollo Scientific Ltd 713-bromo-N-methyl-4- {[(4-methyl-2- pyridinyl)methyl]oxy} benzamide 2-(chloromethyl)- 4- methylpyridine, hydrochloride

0.54 g LCMS (Method B): Rt = 6.44 min, [MH]+ = 335, 337 Intermediate 6572 3-bromo-4-{[(4-methyl- 2- pyridinyl)methyl]oxy} benzamide 2-(chloromethyl)- 4- methylpyridine, hydrochloride

0.49 g LCMS (Method A): Rt = 6.20 min, [MH]+ = 321, 323 Intermediate 6773 3-bromo-N,N-dimethyl- 4-{[(4-methyl-2- pyridinyl)methyl]oxy}benzamide 2- (chloromethyl)- 4- methylpyridine, hydrochloride

0.51 g LCMS (Method B): Rt = 6.54 min, [MH]+ = 349, 351 Intermediate 6674 2-({[2-bromo-3,4- bis(methyloxy)phenyl] oxy}methyl)-4- methylpyridine2- (chloromethyl)- 4- methylpyridine, hydrochloride

0.547 g  LCMS (Method B): Rt = 5.07 min, [MH]+ = 338, 340 Intermediate70 75 2-{[(2-bromo-4- chlorophenyl)oxy] methyl}-4- methylpyridine 2-(chloromethyl)- 4- methylpyridine, hydrochloride

0.63 g LCMS (Method A): Rt = 7.75 min, [MH]+ = 313.85 Commercial egAldrich 85 2-bromo-6-methyl-3- ({[4-(methyloxy)-2- pyridinyl]methyl}oxy)pyridine 2- (chloromethyl)- 4- (methyloxy) pyridine

1.80 g ¹H NMR (400 MHz, DMSO-d6) δ ppm 8.40 (1H, d, CH), 7.52 (1H, d,CH), 7.24 (1H, d, CH), 7.14 (1H, d, CH), 6.96 (1H, s), 6.95 (1H, m, 1H),5.23 (2H, s, CH₂), 3.85 (3H, s, OMe), 2.39 (3H, s, Me) 862-bromo-6-chloro-3- {[(4-methyl-2- pyridinyl)methyl]oxy} pyridine 2-(chloromethyl)- 4- methylpyridine, hydrochloride

0.21 g LCMS (Method A): Rt = 6.92 min, [MH]+ = 314.85 Commercial e.g.Combi-Blocks Inc. 87 2-({[2-bromo-3- (methyloxy)phenyl]oxy}methyl)pyrazine 2- (chloromethyl) pyrazine

2.10 g LCMS (Method C): Rt = 1.51 min, [MH]+ = 295, 296.9 *Intermediate8 was purified by column chromatography, eluting with 0-20% ethylacetate in hexane *Purified through silica eluting with a gradient ofethyl acetate in hexane, increasing ethyl acetate until product eluted#Work up by partitioning between ethyl acetate and aqueous ammoniumchloride. Organics dried with sodium sulphate and concentrated in vacuoto yield the title compound.

Intermediate 34,1-(3-bromo-4-{[(4-chloro-2-pyridinyl)methyl]oxy}phenyl)ethanone

To a stirred solution of (4-chloro-2-pyridinyl)methanol (Commercial egAldrich) (0.2 g) in THF (5 ml) were added1-(3-bromo-4-hydroxyphenyl)ethanone (0.3 g) and triphenylphosphine(0.547 g). This was stirred for 10 min before cooling and adding slowlyDEAD (0.363 g). This was stirred for 16 h. The reaction mixture waspartitioned between water and ethyl acetate. The aqueous was reextractedwith ethyl acetate and the combined organics were washed with brine,dried over sodium sulfate and concentrated in vacuo. This was purifiedthrough silica eluting with 0-35% ethyl acetate in hexane to give thetitle compound, 0.30 g

Mass Spec: [MH]+=340, 342

Prepared similarly were:

Intermediate Alcohol Phenol Amount Characterisation 351-(3-bromo-4-{[(4-ethyl- 2- pyridinyl)methyl]oxy} phenyl)ethanone(4-ethyl-2- pyridinyl)methanol

0.45 g Mass Spec: [MH]+ = 333.9 36 2-bromo-3-{[(4-ethyl-2-pyridinyl)methyl]oxy}- 6-methylpyridine (4-ethyl-2- pyridinyl)methanol

 4.0 g LCMS (Method B): Rt = 5.08 min, [MH]+ = 307, 309

Intermediate 10: 1,1-dimethylethyl7-[3-{](4-methyl-2-pyridinyl)methyl]oxy}-2-pyridinyl)-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate

To a degassed mixture of2-bromo-3-{[(4-methyl-2-pyridinyl)methyl]oxy}pyridine (2.83 g),1,1-dimethylethyl7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate(4.54 g) and cesium carbonate (9.9 g) in dioxane:water (4:1, 40 ml) wasadded PdCl₂.dppf (0.828 g). The reaction mixture was heated at 120° C.overnight. The reaction mixture was added to water and extraction wascarried out with ethyl acetate. The organic layer was dried over sodiumsulphate and the filtrate was concentrated in vacuo. The crude productwas purified through silica, eluting with 0-40% ethyl acetate in hexane.Appropriate fractions were concentrated in vacuo to yield the titlecompound, 3.8 g (84%).

LCMS (Method A): Rt=5.70 min, [MH]+=446

The following intermediates were similarly prepared:

Intermediate Aromatic bromide Purification Amount Characterisation 111,1-dimethylethyl 7- (2-(methyloxy)-6-{[(4- methyl-2-pyridinyl)methyl]oxy} phenyl)-1,2,4,5- tetrahydro-3H-3- benzazepine-3-carboxylate

0-15% ethyl acetate in hexane 2.57 g (89%) LCMS (Method A): Rt = 6.76min, [MH]+ = 475 12 1,1-dimethylethyl 7- (4-(methyloxy)-2-{[(4-methyl-2- pyridinyl)methyl]oxy} phenyl)-1,2,4,5- tetrahydro-3H-3-benzazepine-3- carboxylate

0-20% ethyl acetate in hexane  4.8 g (quant.) LCMS (Method A): Rt = 7.13min, [MH]+ = 475 13 1,1-dimethylethyl 7- (5-acetyl-2-{[(4- methyl-2-pyridinyl)methyl]oxy} phenyl)-1,2,4,5- tetrahydro-3H-3- benzazepine-3-carboxylate

0-20% ethyl acetate in hexane  3.0 g (77%) LCMS (Method A): Rt = 6.77min, [MH]+ = 487 14 1,1-dimethylethyl 7- [2-({[4-(methyloxy)-2-pyridinyl]methyl}oxy) phenyl]-1,2,4,5- tetrahydro-3H-3- benzazepine-3-carboxylate

0-20% ethyl acetate in hexane  3.1 g (71%) LCMS (Method A): Rt = 6.23min, [MH]+ = 461 37 1,1-dimethylethyl 7- (6-(1,1-dimethylethyl)-3-{[(4-methyl-2- pyridinyl)methyl]oxy}- 2-pyridinyl)-1,2,4,5-tetrahydro-3H-3- benzazepine-3- carboxylate

0-15% ethyl acetate in hexane  3.7 g Mass Spec: [MH]+ = 502 381,1-dimethylethyl 7- (6-methyl-3-{[(4- methyl-2- pyridinyl)methyl]oxy}-2-pyridinyl)-1,2,4,5- tetrahydro-3H-3- benzazepine-3- carboxylate

0-40% EA/hexane   15 g Mass Spec: [MH]+ = 460.2 LCMS (Method A): Rt =7.40 min, [MH]+ = 460 39 1,1-dimethylethyl 7- (3-{[(4-ethyl-2-pyridinyl)methyl]oxy}- 6-methyl-2-pyridinyl)- 1,2,4,5-tetrahydro-3H-3-benzazepine-3- carboxylate

0-20% EA/hexane  4.3 g Mass Spec: [MH]+ = 474 40 1,1-dimethylethyl 7-(5-methyl-2-{[(4- methyl-2- pyridinyl)methyl]oxy} phenyl)-1,2,4,5-tetrahydro-3H-3- benzazepine-3- carboxylate

0-15% EA/hexane 0.271 g  LCMS (Method A): Rt = 8.21 min, [MH]+ = 459.1541 1,1-dimethylethyl 7- (5-(ethyloxy)-2-{[(4- methyl-2-pyridinyl)methyl]oxy} phenyl)-1,2,4,5- tetrahydro-3H-3- benzazepine-3-carboxylate

0-15% EA/hexane 0.241 g  LCMS (Method B): Rt = 8.06 min, [MH]+ = 489.2542 1,1-dimethylethyl 7- (5-fluoro-2-{[(4- methyl-2-pyridinyl)methyl]oxy} phenyl)-1,2,4,5- tetrahydro-3H-3- benzazepine-3-carboxylate

0-25% EA/hexane 0.304 g  LCMS (Method A): Rt = 7.97 min, [MH]+ = 463.2543 1,1-dimethylethyl 7- (5-cyano-2-{[(4- methyl-2- pyridinyl)methyl]oxy}phenyl)-1,2,4,5- tetrahydro-3H-3- benzazepine-3- carboxylate

0-30% EA/hexanes 0.24 g LCMS (Method B): Rt = 7.60 min, [MH]+ = 470.2 441,1-dimethylethyl 7- (5-(1,1-dimethylethyl)- 2-{[(4-methyl-2-pyridinyl)methyl]oxy} phenyl)-1,2,4,5- tetrahydro-3H-3- benzazepine-3-carboxylate

0-37% EA/hexane 0.296 g  LCMS (Method A): Rt = 8.53 min, [MH]+ = 501.345 1,1-dimethylethyl 7- [2-{[(4-methyl-2- pyridinyl)methyl]oxy}- 5-(trifluoromethyl)phenyl]- 1,2,4,5-tetrahydro- 3H-3-benzazepine-3-carboxylate

0-18% EA/hexane 0.315 g  LCMS (Method A): Rt = 8.06 min, [MH]+ = 513.276 1,1-dimethylethyl 7- (5- [(methylamino)carbonyl]- 2-{[(4-methyl-2-pyridinyl)methyl]oxy} phenyl)-1,2,4,5- tetrahydro-3H-3- benzazepine-3-carboxylate

0-2% methanol in DCM 0.28 g LCMS (Method A): Rt = 9.03 min, [MH]+ = 50277 1,1-dimethylethyl 7- (5-(aminocarbonyl)-2- {[(4-methyl-2-pyridinyl)methyl]oxy} phenyl)-1,2,4,5- tetrahydro-3H-3- benzazepine-3-carboxylate

0-2% methanol in DCM 0.297 g  LCMS (Method A): Rt = 7.13 min, [MH]+ =488 78 1,1-dimethylethyl 7- (2,3-bis(methyloxy)-6- {[(4-methyl-2-pyridinyl)methyl]oxy} phenyl)-1,2,4,5- tetrahydro-3H-3- benzazepine-3-carboxylate

0-20% EA/hexane 0.225 g  LCMS (Method A): Rt = 6.59 min, [MH]+ = 505 791,1-dimethylethyl 7- (5-chloro-2-{[(4- methyl-2- pyridinyl)methyl]oxy}phenyl)-1,2,4,5- tetrahydro-3H-3- benzazepine-3- carboxylate

0-25% EA/hexane 0.24 g LCMS (Method A): Rt = 8.17 min, [MH]+ = 479.15 881,1-dimethylethyl 7- (6-chloro-3-{[(4- methyl-2- pyridinyl)methyl]oxy}-2-pyridinyl)-1,2,4,5- tetrahydro-3H-3- benzazepine-3- carboxylate

0-25% EA/hexane 0.094 g  LCMS (Method B): Rt = 7.76 min, [MH]+ = 480.1589 1,1-dimethylethyl 7- {2′-(methyloxy)-6′-[(2- pyrazinylmethyl)oxy]-4-biphenylyl}-1,2,4,5- tetrahydro-3H-3- benzazepine-3- carboxylate

25% EA/hexane  1.0 g LCMS (Method C): Rt = 1.77 min, [MH]+ = 462.2

The following intermediate was prepared similarly using1,1-dimethylethyl7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2(1H)-isoquinolinecarboxylaterather than 1,1-dimethylethyl7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate

90 1,1-dimethylethyl 7- (6-chloro-3-{[(4- methyl-2-pyridinyl)methyl]oxy}- 2-pyridinyl)-3,4- dihydro-2(1H)-isoquinolinecarboxylate

0-35% EA/ hexane 0.037 g LCMS (Method B): Rt = 7.59 min, [MH]+ = 480.15

Intermediate 15: 1,1-dimethylethyl7-(5-fluoro-2-{[4-methyl-2-pyridinyl)methyl]oxy}phenyl)-3,4-dihydro-2(1H)-isoquinolinecarboxylate

To a degassed mixture2-{[(2-bromo-4-fluorophenyl)oxy]methyl}-4-methylpyridine (0.09 g),1,1-dimethylethyl7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2(1H)-isoquinolinecarboxylate(0.131 g) (for preparation see WO 2007/056710) and caesium carbonate(0.296 g) in dioxane:water (4:1, 5 ml) was added PdCl₂.dppf (0.025 g).The reaction mixture was heated at 120° C. overnight. The reactionmixture was added to water and extraction was carried out with ethylacetate. The organic layer was dried over sodium sulphate and thefiltrate was concentrated in vacuo. The crude product was purifiedthrough silica, eluting with 0-12% ethyl acetate in hexane. Appropriatefractions were concentrated in vacuo to yield the title compound, 0.169g, quantitative yield.

LCMS (Method B): Rt=7.95 min, [MH]+=449

The following intermediates were similarly prepared:

Intermediate Aromatic bromide Amount Characterisation 461,1-dimethylethyl 7-(5- methyl-2-{[(4-methyl-2- pyridinyl)methyl]oxy}phenyl)-3,4-dihydro-2(1H)- isoquinolinecarboxylate

0.157 g LCMS (Method A): Rt = 8.20 min, [MH]+ = 445.15 471,1-dimethylethyl 7-(5- (methyloxy)-2-{[(4-methyl-2-pyridinyl)methyl]oxy} phenyl)-3,4-dihydro-2(1H)-isoquinolinecarboxylate

0.137 g LCMS (Method A): Rt = 7.89 min, [MH]+ = 461.2 481,1-dimethylethyl 7-[2-{[(4- methyl-2- pyridinyl)methyl]oxy}-5-(trifluoromethyl)phenyl]- 3,4-dihydro-2(1H)- isoquinolinecarboxylate

0.153 g LCMS (Method B): Rt = 8.05 min, [MH]+ = 499.15 491,1-dimethylethyl 7-(2- (methyloxy)-6-{[(4-methyl-2-pyridinyl)methyl]oxy} phenyl)-3,4-dihydro-2(1H)-isoquinolinecarboxylate

0.145 g LCMS (Method A): Rt = 7.71 min, [MH]+ = 461 50 1,1-dimethylethyl7-(5- cyano-2-{[(4-methyl-2- pyridinyl)methyl]oxy}phenyl)-3,4-dihydro-2(1H)- isoquinolinecarboxylate

0.139 g LCMS (Method A): Rt = 7.55 min, [MH]+ = 456.15 511,1-dimethylethyl 7-(5- (ethyloxy)-2-{[(4-methyl-2-pyridinyl)methyl]oxy} phenyl)-3,4-dihydro-2(1H)- isoquinolinecarboxylate

0.128 g LCMS (Method B): Rt = 8.05 min, [MH]+ = 475 52 1,1-dimethylethyl7-(5- (1,1-dimethylethyl)-2-{[(4- methyl-2- pyridinyl)methyl]oxy}phenyl)-3,4-dihydro-2(1H)- isoquinolinecarboxylate

  0.13 g LCMS (Method A): Rt = 8.54 min, [MH]+ = 487.2 801,1-dimethylethyl 7-(5- [(dimethylamino)carbonyl]- 2-{[(4-methyl-2-pyridinyl)methyl]oxy} phenyl)-3,4-dihydro-2(1H)- isoquinolinecarboxylate

  0.21 g LCMS (Method B): Rt = 7.17 min, [MH]+ = 502 811,1-dimethylethyl 7-(5- (aminocarbonyl)-2-{[(4- methyl-2-pyridinyl)methyl]oxy} phenyl)-3,4-dihydro-2(1H)- isoquinolinecarboxylate

  0.40 g LCMS (Method A): Rt = 5.30 min, [MH]+ = 474 821,1-dimethylethyl 7-(2,3- bis(methyloxy)-6-{[(4- methyl-2-pyridinyl)methyl]oxy} phenyl)-3,4-dihydro-2(1H)- isoquinolinecarboxylate

  0.21 g LCMS (Method A): Rt = 6.40 min, [MH]+ = 491 831,1-dimethylethyl 7-(5- chloro-2-{[(4-methyl-2- pyridinyl)methyl]oxy}phenyl)-3,4-dihydro-2(1H)- isoquinolinecarboxylate

  0.28 g LCMS (Method B): Rt = 8.10 min, [MH]+ = 465.1

Intermediate 16: 1,1-dimethylethyl7-{5-acetyl-2-[(2-pyrazinylmethyl)oxy]phenyl}-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate

To a stirred solution of1-{3-bromo-4-[(2-pyrazinylmethyl)oxy]phenyl}ethanone (0.2 g) and1,1-dimethylethyl7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate(0.34 g) in DME (4 ml) was added aqueous sodium carbonate (2M, 0.98 ml).This was degassed with nitrogen for 15 min before adding Tetrakis (37mg). The reaction was heated under reflux overnight. TLC indicated thereaction had gone to completion and so it was cooled, diluted with waterand extracted with ethyl acetate. The combined organics were dried oversodium sulphate and concentrated in vacuo to yield a crude product whichwas purified by column chromatography, eluting with 0-18% ethyl acetatein hexane. The appropriate fractions were concentrated in vacuo to yieldthe title compound, 0.093 g, 30% yield.

Mass Spec.: [MH]+=474.2

Intermediate 17 was similarly prepared using different aromaticbromides:

Intermediate Aromatic bromide Purification Amount Characterisation 171,1-dimethylethyl 7-{5-acetyl-2-[(2- pyridinylmethyl) oxy]phenyl}-1,2,4,5- tetrahydro-3H-3- benzazepine-3- carboxylate

0-18% ethyl acetate in hexane 0.056 g (50.5%) Mass Spec: [MH]+ = 473.253 1,1-dimethylethyl 7-{6-methyl-3-[(2- pyrazinylmethyl)oxy]-2-pyridinyl}- 1,2,4,5- tetrahydro-3H-3- benzazepine-3-

EA/hexane 0.247 g Mass Spec: [MH]+ = 447.2 carboxylate 541,1-dimethylethyl 7-{5-(methyloxy)- 2-[(2- pyrazinylmethyl) oxy]phenyl}-1,2,4,5- tetrahydro-3H-3-

EA/hexane 0.193 g Mass Spec: [MH]+ = 462.2 benzazepine-3- carboxylate 551,1-dimethylethyl 7-[5-(methyloxy)- 2-({[4- (methyloxy)-2-pyridinyl]methyl} oxy)phenyl]- 1,2,4,5- tetrahydro-3H-3- benzazepine-3-carboxylate

EA/hexane 0.268 g Mass Spec: [MH]+ = 491.3 56 1,1-dimethylethyl7-(5-(methyloxy)- 2-{[(4-methyl-2- pyridinyl)methyl] oxy}phenyl)-1,2,4,5- tetrahydro-3H-3- benzazepine-3- carboxylate

EA/hexane 0.273 g Mass Spec: [MH]+ = 475.3 57 1,1-dimethylethyl7-[5-acetyl-2-({[4- (methyloxy)-2- pyridinyl]methyl} oxy)phenyl]-1,2,4,5- tetrahydro-3H-3- benzazepine-3- carboxylate

EA/hexane 0.291  Mass Spec: [MH]+ = 503.2 58 1,1-dimethylethyl7-(5-acetyl-2-{[(4- chloro-2- pyridinyl)methyl] oxy}phenyl)- 1,2,4,5-tetrahydro-3H-3- benzazepine-3- carboxylate

EA/hexane  0.97 g Mass Spec: [MH]+ = 507.2 59 1,1-dimethylethyl7-(5-acetyl-2-{[(4- ethyl-2- pyridinyl)methyl] oxy}phenyl)- 1,2,4,5-tetrahydro-3H-3- benzazepine-3- carboxylate

0-4% MeOH in DCM 0.217 g Mass Spec: [MH]+ = 501.2 91 1,1-dimethylethyl7-[6-methyl-3- ({[4-(methyloxy)- 2-pyridinyl]methyl} oxy)-2-pyridinyl]-1,2,4,5- tetrahydro-3H-3- benzazepine-3- carboxylate

EA/hexane 0.283 g Mass Spec: [MH]+ = 476.2

The following intermediate was prepared similarly using1,1-dimethylethyl7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2(1H)-isoquinolinecarboxylaterather than 1,1-dimethylethyl7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate

84 1,1-dimethylethyl 7-{5- acetyl-2-[(2- pyridinylmethyl)oxy]phenyl}-3,4-dihydro-2(1H)- isoquinolinecarboxylate

0.222 g Mass Spec: [MH]+ = 459.1

The following intermediate was prepared similarly using1,1-dimethylethyl5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-dihydro-2H-isoindole-2-carboxylate(Preparation e.g. WO2010145202) rather than 1,1-dimethylethyl7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate

92 1,1-dimethylethyl 5-{5- acetyl-2-[(2- pyridinylmethyl)oxy]phenyl}-1,3-dihydro-2H- isoindole-2-carboxylate

0.24 g Mass Spec: [MH]+ = 473.2

The following intermediate was prepared similarly using1,1-dimethylethyl6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2(1H)-isoquinolinecarboxylate(preparation e.g. WO2008079277) rather than 1,1-dimethylethyl7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate

93 1,1-dimethylethyl 6-{5- acetyl-2-[(2- pyridinylmethyl)oxy]phenyl}-1-3,4-dihydro-2(1H)- isoquinolinecarboxylate

0.284 g Mass Spec: [MH]+ = 459.2

Intermediate 60, 2-bromo-5-[(phenylmethyl)oxyl]pyridine

To a stirred solution of 6-bromo-3-pyridinol (10 g, Commercial eg ApolloScientific Ltd.) in DMF (100 ml) was added potassium carbonate (17.8 g).The reaction mixture was stirred for 15 min at 25-30C before cooling to15° C. To this was added slowly benzyl bromide (7.5 ml) and this wasstirred at 25-30° C. for 48 h. The reaction mixture was poured into coldwater and the solid was collected by filtration to give the titlecompound, 14.5 g

Mass Spec: [MH]+=265.9

Intermediate 61, 2-(1,1-dimethylethyl)-5-[(phenylmethyloxy]pyridine

To a stirred solution of copper (I) cyanide (18.31 g) in dry THF (400ml) was added, at −78C, tertbutylmagnesium chloride (1M in THF, 409 ml).The reaction mixture was stirred at this temperature for 15 min beforeslowly adding a solution of 2-bromo-5-[(phenylmethyl)oxy]pyridine (13.5g) in THF. This was stirred for 2 h at −78C before warming to 25-30C andstirring for a further 20 h. The reaction mixture was poured into waterand extracted with ethyl acetate. This was concentrated in vacuo andpurified through silica, eluting with 0-2% ethyl acetate in hexane.Appropriate fractions were combined and concentrated in vacuo to yieldthe title compound, 6.3 g

LCMS (Method B): Rt=5.61 min, [MH]+=242

Intermediate 62, 6-(1,1-dimethylethyl)-3-pyridinol

To a stirred solution of2-(1,1-dimethylethyl)-5-[(phenylmethyl)oxy]pyridine , (5.3 g) in ethanol(150 ml) was added 20% Pd(OH)₂ (12.3 g) at 25-30C. The above mixture waspurged with hydrogen for 3 h until it had gone to completion by tic. Thereaction mixture was filtered through celite and the filtrateconcentrated in vacuo and purified to give the title compound, 3.9 g

LCMS (Method B): Rt=3.14 min, [MH]+=152

Intermediate 63, 2-bromo-6-(1,1-dimethylethyl)-3-pyridinol

To a stirred solution of 6-(1,1-dimethylethyl)-3-pyridinol, (3.8 g) inpyridine (150 ml) was added bromine (1.29 ml), diluted in pyridine,dropwise at 20C. The reaction mixture was allowed to stir at 25-30C for1 h. The reaction had gone to completion by tlc. It was poured intobrine and extracted with ethyl acetate. The organics were dried oversodium sulphate and concentrated under reduced pressure. The crudematerial was subjected to flash chromatography using a 0-5% gradient ofethyl acetate in hexane to give the title compound, 2.9 g

LCMS (Method B): Rt=6.16 min, [MH]+=229.9

Intermediate 64 1,1-dimethylethyl7-[5-acetyl-2-({[4-(ethyloxy)-2-pyridinyl]methyl}oxy)phenyl]-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate

Potassium tert-butoxide (0.132 g) in ethanol (4 ml) was stirred for 15min before adding 1,1-dimethylethyl7-(5-acetyl-2-{[(4-chloro-2-pyridinyl)methyl]oxy}phenyl)-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate, (0.4 g) and this was heated in a microwave at 110C for 1.5 h. Water(20 ml) was added to the cooled mixture and this was extracted with DCM(2×30 ml). The combined organics were washed with brine, dried oversodium sulphate and concentrated in vacuo. The crude product waspurified through silica eluting with 0-45% ethyl acetate in hexane togive the title compound, 0.16 g

Mass Spec: [MH]+=517.3

Prepared similarly was Intermediate:

Intermediate Starting Materials Amount LCMS 94 1,1-dimethylethyl7-(5-acetyl-2-{[(4- {[2-(methyloxy)ethyl] oxy}-2- pyridinyl)methyl]oxy}phenyl)- 1,2,4,5- tetrahydro-3H-3- benzazepine-3- carboxylate

and MeO(CH₂)₂OH 0.045 g Mass Spec: [MH]+ = 547.3

Example 17-(3-{[(4-methyl-2-pyridinyl)methyl]oxy}-2-pyridinyl)-2,3,4,5-tetrahydro-1H-3-benzazepine

1,1-dimethylethyl7-(3-{[(4-methyl-2-pyridinyl)methyl]oxy}-2-pyridinyl)-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate(3.8 g) was dissolved in dioxane (20 ml). Gaseous hydrogen chloride waspassed through the reaction mixture for 1.5 h. The reaction wasmonitored by TLC. On completion the solid formed was collected byfiltration and washed with acetone. The solid was then dissolved inwater and the mixture neutralised with aqueous sodium hydroxide (1M).The sticky solid formed was extracted with DCM. The organic phase wasdried over sodium sulphate and concentrated in vacuo to give a solid.This was purified through silica, eluting the product with 0-12%methanol in DCM. The solid from this was triturated in diethyl ether togive the title compound, 2 g (69%) yield.

LCMS (Method A): Rt=3.25 min, [MH]+=346

NMR ¹H NMR (400 MHz, DMSO-d6) δ ppm 8.43 ppm (1H, d, CH), 8.27 ppm (1H,d, CH), 7.77 ppm (1H, s, CH), 7.70-7.64 ppm (2H, 2×d, 2×CH), 7.35 ppm(2H, m, 2×CH), 7.20 ppm (2H, m, 2×CH), 5.23 ppm (2H, s, CH₂), 2.97 ppm(8H, br.m, ⁴×CH₂), 2.32 ppm (3H, s, CH₃)

Example 27-(2-(methyloxy)-6-{[(4-methyl-2-pyridinyl)methyl]oxy}phenyl)-2,3,4,5-Tetrahydro-1H-3-benzazepine

1,1-dimethylethyl7-(2-(methyloxy)-6-{[(4-methyl-2-pyridinyl)methyl]oxy}phenyl)-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate(2.57 g) was dissolved in dioxane (20 ml). Gaseous hydrogen chloride waspassed through the reaction mixture for about 1.5 h. The reaction wasmonitored by TLC. On completion the solid formed was collected byfiltration and washed with acetone. The solid was then dissolved inwater and the mixture neutralised with aqueous sodium hydroxide (1M).The sticky solid formed was extracted with DCM. The organic phase wasdried over sodium sulphate and concentrated in vacuo to give a solid.This was purified by silica column chromatography eluting with 0-8%methanol in DCM. The appropriate fractions were combined andconcentrated in vacuo to yield a solid. This was triturated with diethylether to yield the title compound, 1.34 g (67%).

LCMS (Method A): Rt=3.89 min, [MH]+=375

NMR ¹H NMR (400 MHz, DMSO-d6) δ ppm 8.35 ppm (1H, d, CH), 7.24 ppm (1H,m, CH), 7.21-7.08 ppm (4H, m, 4×CH), 6.94 ppm (1H, br.s, CH), 6.78 ppm(2H, m, 2×CH), 5.10 ppm (2H, s, CH₂), 3.68 ppm (3H, s, OCH₃), 3.09 ppm(8H, br.m, 4×CH₂), 2.23 ppm (3 h, S, CH₃)

Example 2A7-(2-(methyloxy)-6-{[(4-methyl-2-pyridinyl)methyl]oxy}phenyl)-2,3,4,5-tetrahydro-1H-3-benzazepinemethanesulfonate

7-(2-(methyloxy)-6-{[(4-methyl-2-pyridinyl)methyl]oxy}phenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine(300.0 mg; 1.0 eq) was weighed into a 20-mL vial containing a stir barand combined with 2-propanol (6.0 mL). The suspension was heated to 40°C. and stirred for 15 min (solids dissolved). Seeds of themethanesulfonate salt were added (˜1 mg). Methanesulfonic acid (3M inwater; 1.1 eq.; 293.0 uL in aliquots: 43, 50, 100, and 100 μL) wasadded. White solid precipitated after the first aliquot (43 μL). Thesuspension was re-seeded with the methansulfonate salt (˜1 mg). Afterall aliquots of the counterion solution were added, the suspension wasstirred at 40° C. for 1 hr. The suspension was cooled to 5° C. at 0.5°C./min and stirred for 15 min. The product was isolated on a Büchnerfunnel using #1 Whatman filter paper, air-dried for 30 min, and dried at40° C. under vacuum for 12 hrs. The title compound was produced as awhite crystalline powder. A yield of 82% was obtained.

Example 37-(4-(methyloxy)-2-{[(4-methyl-2-pyridinyl)methyl]oxy}phenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine

1,1-dimethylethyl7-(4-(methyloxy)-2-{[(4-methyl-2-pyridinyl)methyl]oxy}phenyl)-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate(4.8 g) was dissolved in dioxane (20 ml). Gaseous hydrogen chloride waspassed through the reaction mixture for 1.5 h. The reaction wasmonitored by TLC. On completion the solid formed was collected byfiltration and washed with acetone. The solid was then dissolved inwater and the mixture was brought to pH8 using aqueous sodiumbicarbonate. The sticky solid observed was extracted with DCM. Theorganics were dried over sodium sulphate and concentrated in vacuo toyield a solid. This was purified by column chromatography eluting with0-8% methanol in DCM. Appropriate fractions were combined andconcentrated in vacuo to yield a solid. This was triturated in diethylether to yield the title compound, 1.7 g (45%).

LCMS (Method A): Rt=4.11 min, [MH]+=375

NMR ¹H NMR (400 MHz, DMSO-d6) δ ppm 8.41 ppm (1H, d, CH), 7.38 ppm (1H,br.s, CH), 7.29-7.23 ppm (3H, m, 3×CH), 7.19-7.15 ppm (2H, m, 2×CH),6.76 ppm (1H, br.s, CH), 6.63 ppm (1H, d, CH), 5.14 ppm (2H, s, CH₂),3.79 ppm (3H, s, OCH₃), 3.00 ppm (8H, br.m, 4×CH₂), 2.30 ppm (3H, s,CH₃)

Example 41-[4-{[(4-methyl-2-pyridinyl)methyl]oxy}-3-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)phenyl]ethanone

1,1-dimethylethyl7-(5-acetyl-2-{[(4-methyl-2-pyridinyl)methyl]oxy}phenyl)-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate(3.0 g) was dissolved in dioxane (20 ml).

Gaseous hydrogen chloride was passed through the reaction mixture for1.5 h. The reaction was monitored by TLC. On completion the solid formedwas collected by filtration and washed with acetone. The solid was thendissolved in water and the mixture neutralised with aqueous sodiumhydroxide (1M). Solid was obtained which was collected by filtration.This was triturated with diethyl ether to yield the title compound, 2.1g (88%).

LCMS (Method A): Rt=3.77 min, [MH]+=387

NMR ¹H NMR (400 MHz, DMSO-d6) δ ppm 8.42 ppm (1H, d, CH), 7.98 ppm (1H,d, CH), 7.95 ppm (1H, s, CH), 7.42 ppm (1H, br.s, CH), 7.36-7.30 ppm(2H, m, 2×CH), 7.25-7.17 ppm (3H, m, 3×CH), 5.26 ppm (2H, s, CH₂), 2.94ppm (8H, m, 4×CH₂), 2.57 ppm (3H, s, CH₃), 2.26 ppm (3H, s, CH₃)

Prepared similarly were the following examples:

Example Starting Material Amount Characterisation 9 7-(6-methyl-3-{[(4-methyl-2- pyridinyl)methyl] oxy}-2-pyridinyl)- 2,3,4,5-tetrahydro-1H-3- benzazepine

1.35 g Mass Spec.: [MH]+ = 360.1 HPLC: Rt = 5.28 min

Example 51-[4-[(2-pyrazinylmethyl)oxy]-3-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)phenyl]ethanone,trifluoroacetate

To a stirred solution of 1,1-dimethylethyl7-{5-acetyl-2-[(2-pyrazinylmethyl)oxy]phenyl}-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate(0.093 g) in DCM (2 ml) at 0° C. was added dropwise trifluoroacetic acid(0.08 ml). This was stirred at room temperature overnight. The reactionhad gone to completion by TLC and so was concentrated in vacuo andazeotroped with diethyl ether (5×10 ml). The compound obtained waswashed with diethyl ether and pentane to yield a crude compound that waspurified by preparative HPLC. Appropriate fractions were concentrated invacuo to yield the title compound as the TFA salt, 0.040 g.

NMR ¹H NMR (400 MHz, DMSO-d6) δ ppm 8.88 (br. s., 2 H), 8.71 (s, 1 H),8.68 (d, J=2.3 Hz, 1H), 8.62 (d, J=2.3 Hz, 1H), 8.00 (dd, J=8.6, 2.0 Hz,1H), 7.89 (d, J=2.3 Hz, 1H), 7.49 (s, 1H), 7.45 (d, J=7.8 Hz, 1H), 7.38(d, J=8.8 Hz, 1H), 7.29 (d, J=7.8 Hz, 1H), 5.41 (s, 2H), 3.19-3.27 (m,4H), 3.04-3.17 (m, 4H), 2.58 (s, 3H)

Mass Spec.: [MH]+=374.1

Example 67-(5-fluoro-2-{[(4-methyl-2-pyridinyl)methyl]oxy}phenyl)-1,2,3,4-tetrahydroisoquinoline

1,1-Dimethylethyl7-(5-fluoro-2-{[(4-methyl-2-pyridinyl)methyl]oxy}phenyl)-3,4-dihydro-2(1H)-isoquinolinecarboxylate(0.169 g) was dissolved in dioxane (1 ml). This was ice cooled beforeadding dropwise a solution of hydrogen chloride in dioxane (2 ml). Thiswas stirred at room temperature overnight before concentrating in vacuo.The residue obtained was dissolved in water and backwashed with ethylacetate. The aqueous layer was neutralised with aqueous sodium hydroxide(1M) and extracted with ethyl acetate. The organics were concentrated invacuo and purified by preparative HPLC. Appropriate fractions wereconcentrated, neutralised with aqueous sodium bicarbonate and extractedwith ethyl acetate. The organics were concentrated in vacuo to yield thetitle compound, 0.061 g (47%).

LCMS (Method A): Rt=6.37 min, [MH]+=349

Prepared similarly were the following examples:

Example Starting Material Amount LCMS 10 7-(5-methyl-2- {[(4-methyl-2-pyridinyl)methyl] oxy}phenyl)- 1,2,3,4- tetrahydroisoquinoline

   72 mg LCMS (Method B): Rt = 6.61 min, [MH]+ = 345 117-(2-(methyloxy)- 6-{[(4-methyl-2- pyridinyl)methyl] oxy}phenyl)-1,2,3,4- tetrahydroisoquinoline

   46 mg LCMS (Method B): Rt = 6.06 min, [MH]+ = 361.1 127-(5-(ethyloxy)-2- {[(4-methyl-2- pyridinyl)methyl] oxy}phenyl)-1,2,3,4- tetrahydroisoquinoline

   50 mg LCMS (Method A): Rt = 6.59 min, [MH]+ = 375 14 4-{[(4-methyl-2-pyridinyl)methyl] oxy}-3-(1,2,3,4- tetrahydro-7- isoquinolinyl)benzonitrile

   50 mg LCMS (Method A): Rt = 5.94 min, [MH]+ = 356 157-[2-{[(4-methyl- 2-pyridinyl)methyl] oxy}-5- (trifluoromethyl)phenyl]-1,2,3,4- tetrahydroisoquinoline

   84 mg LCMS (Method B): Rt = 6.72 min, [MH]+ = 399.1 167-(5-(methyloxy)- 2-{[(4-methyl-2- pyridinyl)methyl] oxy}phenyl)-1,2,3,4- tetrahydroisoquinoline

   84 mg LCMS (Method A): Rt = 6.18 min, [MH]+ = 361.1 17 7-(5-(1,1-dimethylethyl)-2- {[(4-methyl-2- pyridinyl)methyl] oxy}phenyl)- 1,2,3,4-tetrahydroisoquinoline

   45 mg LCMS (Method B): Rt = 7.10 min, [MH]+ = 387.2 39N-methyl-4-{[(4- methyl-2- pyridinyl)methyl] oxy}-3-(2,3,4,5-tetrahydro-1H-3- benzazepin-7- yl)benzamide

0.065 g LCMS (Method A): Rt = 5.38 min, [MH]+ = 402 40 4-{[(4-methyl-2-pyridinyl)methyl] oxy}-3-(2,3,4,5- tetrahydro-1H-3- benzazepin-7-yl)benzamide

 0.1 g LCMS (Method B): Rt = 5.21 min, [MH]+ = 388 41 N,N-dimethyl-4-{[(4-methyl-2- pyridinyl)methyl] oxy}-3-(1,2,3,4- tetrahydro-7-isoquinolinyl) benzamide

 0.06 g LCMS (Method A): Rt = 5.43 min, [MH]+ = 402 42 4-{[(4-methyl-2-pyridinyl)methyl] oxy}-3-(1,2,3,4- tetrahydro-7- isoquinolinyl)benzamide

 0.06 g LCMS (Method A): Rt = 3.01 min, [MH]+ = 374 43 7-(2,3-bis(methyloxy)-6- {[(4-methyl-2- pyridinyl)methyl] oxy}phenyl)- 1,2,3,4-tetrahydroisoquinoline

0.100 g LCMS (Method A): Rt = 3.49 min, [MH]+ = 391 44 7-(2,3-bis(methyloxy)-6- {[(4-methyl-2- pyridinyl)methyl] oxy}phenyl)- 2,3,4,5-tetrahydro-1H-3- benzazepine

 0.07 g LCMS (Method A): Rt = 3.56 min, [MH]+ = 405

Example 77-[2-({[4-(methyloxy)-2-pyridinyl]methyl}oxy)phenyl]-2,3,4,5-tetrahydro-1H-3-benzazepine

To a stirred solution of 1,1-dimethylethyl7-[2-({[4-(methyloxy)-2-pyridinyl]methyl}oxy)phenyl]-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate(3.0 g) in dioxane (30 ml) was added hydrogen chloride gas for 2 h at10-20° C. This was concentrated in vacuo. The residue was dissolved inwater, washed with ethyl acetate and basified by adding aqueous sodiumbicarbonate. This was extracted with 10% methanol in DCM. The organicswere dried over sodium sulphate and concentrated in vacuo to yield thetitle compound, 2.14 g (91%).

LCMS (Method B): Rt=6.18 min, [MH]+=361

Example 81-[4-[(2-pyridinylmethyl)oxy]-3-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)phenyl]ethanone,trifluoroacetate

To a cooled, stirred solution of 1,1-dimethylethyl7-{5-acetyl-2-[(2-pyridinylmethyl)oxy]phenyl}-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate(0.056 g) in DCM (1 ml) was added TFA (0.2 ml). This was stirredovernight. The reaction had gone to completion and so was concentratedin vacuo and tritutrated with pentane/ether to yield the title compoundas the TFA salt, 0.028 g (63.6%).

Mass Spec.: [MH]+=373.1

HPLC: Rt=5.71 min.

Prepared similarly were the following examples:

Example Starting Material Amount Characterisation 18 7-{6-methyl-3-[(2-pyrazinylmethyl) oxy]-2-pyridinyl}- 2,3,4,5- tetrahydro-1H-3-benzazepine, trifluoroacetate

  100 mg HPLC Rt = 5.51 min Mass Spec: [MH]+ = 347.1 19 7-(6-methyl-3-{[(4-methyl-2- pyridinyl)methyl] oxy}-2-pyridinyl)- 2,3,4,5-tetrahydro-1H-3- benzazepine, trifluoroacetate

   22 mg HPLC Rt = 5.23 min Mass Spec: [MH]+ = 360.1 207-{5-(methyloxy)- 2-[(2- pyrazinylmethyl) oxy]phenyl}- 2,3,4,5-tetrahydro-1H-3- benzazepine, trifluoroacetate

   80 mg HPLC Rt = 8.00 min Mass Spec: [MH]+ = 362.1 217-[5-(methyloxy)- 2-({[4- (methyloxy)-2- pyridinyl]methyl} oxy)phenyl]-2,3,4,5- tetrahydro-1H-3- benzazepine

  150 mg (after prep HPLC) HPLC Rt = 6.88 min Mass Spec: [MH]+ = 391.122 7-(5-(methyloxy)- 2-{[(4-methyl-2- pyridinyl)methyl] oxy}phenyl)-2,3,4,5- tetrahydro-1H-3- benzazepine, trifluoroacetate (TFA salt ofexample 29)

   75 mg HPLC Rt = 6.89 min Mass Spec: [MH]+ = 375.1 23 1-[4-({[4-(methyloxy)-2- pyridinyl]methyl} oxy)-3-(2,3,4,5- tetrahydro-1H-3-benzazepin-7- yl)phenyl]ethanone

  120 mg (after prep HPLC) HPLC Rt = 6.55 min Mass Spec: [MH]+ = 403.224 1-[4-{[(4-methyl- 2-pyridinyl)methyl] oxy}-3-(2,3,4,5-tetrahydro-1H-3- benzazepin-7- yl)phenyl]ethanone, trifluoroacetate (TFAsalt of example 4)

   26 mg HPLC Rt = 5.65 min Mass Spec: [MH]+ = 387.1 25 7-[2-({[4-(methyloxy)-2- pyridinyl]methyl} oxy)phenyl]- 2,3,4,5- tetrahydro-1H-3-benzazepine, trifluoroacetate

0.908 g HPLC Rt = 5.92 min Mass Spec: [MH]+ = 361.1 47 7-[6-methyl-3-({[4-(methyloxy)- 2- pyridinyl]methyl} oxy)-2-pyridinyl]- 2,3,4,5-tetrahydro-1H-3- benzazepine

0.118 g (after prep HPLC) HPLC Rt = 4.35 min Mass Spec: [MH]+ = 376.1

Example 267-(5-fluoro-2-{[(4-methyl-2-pyridinyl)methyl]oxy}phenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine

1,1-dimethylethyl7-(5-fluoro-2-{[(4-methyl-2-pyridinyl)methyl]oxy}phenyl)-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate,(0.304 g) was dissolved in a minimum amount of dioxane. The solution wascooled in ice and to this was added a solution of HCl in dioxane (2 ml).This was stirred until the reaction had gone to completion by tic. Thereaction mixture was concentrated in vacuo. The product salt wasdissolved in water and backwashed with ethyl acetate. The aqueous wasneutralised with aqueous sodium hydroxide (1 M). This was extracted withethyl acetate. The organics were dried over sodium sulphate andconcentrated to give the title compound, 100 mg.

LCMS (Method B): Rt=6.34 min, [MH]+=363.1

Prepared similarly were the following examples:

Example Starting Material Amount LCMS 27 7-(5-methyl-2- {[(4-methyl-2-pyridinyl)methyl] oxy}phenyl)- 2,3,4,5- tetrahydro-1H-3- benzazepine

 56 mg LCMS (Method B): Rt = 6.67 min, [MH]+ = 359.2 287-(5-(ethyloxy)-2- {[(4-methyl-2- pyridinyl)methyl] oxy}phenyl)-2,3,4,5- tetrahydro-1H-3- benzazepine

 158 mg LCMS (Method A): Rt = 6.59 min, [MH]+ = 389.2 297-(5-(methyloxy)- 2-{[(4-methyl-2- pyridinyl)methyl] oxy}phenyl)-2,3,4,5- tetrahydro-1H-3- benzazepine

 65 mg LCMS (Method A): Rt = 6.22 min, [MH]+ = 375.1 30 4-{[(4-methyl-2-pyridinyl)methyl] oxy}-3-(2,3,4,5- tetrahydro-1H-3- benzazepin-7-yl)benzonitrile

 70 mg LCMS (Method A): Rt = 5.82 min, [MH]+ = 370.1 31  70 mg LCMS7-[2-{[(4-methyl- (Method A): 2-pyridinyl)methyl] Rt = 6.67 min, oxy}-5-[MH]+ = 413.1 (trifluoromethyl) phenyl]-2,3,4,5- tetrahydro-1H-3-benzazepine 32 7-(5-(1,1- dimethylethyl)-2- {[(4-methyl-2-pyridinyl)methyl] oxy}phenyl)- 2,3,4,5- tetrahydro-1H-3- benzazepine

 144 mg LCMS (Method B): Rt = 7.08 min, [MH]+ = 401.2 45 7-(5-chloro-2-{[(4-methyl-2- pyridinyl)methyl] oxy}phenyl)- 2,3,4,5- tetrahydro-1H-3-benzazepine

0.16 g LCMS (Method B): Rt = 6.71 min, [MH]+ = 379

Example 337-(3-{[(4-ethyl-2-pyridinyl)methyl]oxy}-6-methyl-2-pyridinyl)-2,3,4,5-tetrahydro-1H-3-benzazepine

To a stirred solution of 1,1-dimethylethyl7-(3-{[(4-ethyl-2-pyridinyl)methyl]oxy}-6-methyl-2-pyridinyl)-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate,(4.3 g) in dioxane (30 ml) was passed through HCl (gas) for 30 min at20° C. After completion of reaction by TLC, the solvent was removed invacuo. The solid obtained was washed with acetone and dissolved inwater. This was neutralised with sodium bicarbonate, extracted with DCMand and concentrated in vacuo to give a crude product. This was purifiedthrough silica using 6% methanol in DCM. Appropriate fractions werecombined and concentrated in vacuo to give a product. This wastriturated in diethyl ether to yield the title compound, 1.5 g.

LCMS (Method B): Rt=3.29 min, [MH]+=374

The following example was prepared similarly:

Example Starting Material Amount LCMS 34 7-(6-(1,1- dimethylethyl)-3-{[(4-methyl-2- pyridinyl)methyl] oxy}-2-pyridinyl)- 2,3,4,5-tetrahydro-1H-3- benzazepine

2.7 g LCMS (Method B): Rt = 4.73 min, [MH]+ = 402

Example 351-[4-{[(4-ethyl-2-pyridinyl)methyl]oxy}-3-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)phenyl]ethanone

To a solution of 1,1-dimethylethyl7-(5-acetyl-2-{[(4-ethyl-2-pyridinyl)methyl]oxy}phenyl)-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate,(0.217 g) in DCM (3 ml) was added TFA (0.4 ml). This was stirred at roomtemperature. After completion of reaction by tic, the reaction mixturewas concentrated in vacuo and purified by preparative hplc. Productfractions were concentrated in vacuo and the product obtained waspartitioned between DCM and aqueous sodium bicarbonate. The organicswere dried over sodium sulphate and concentrated in vacuo to yield thetitle compound, 0.035 g

LCMS (Method A): Rt=5.28 min, [MH]+=401.05

HPLC: 6.89 min.

Example 361-[4-({[4-(ethyloxy)-2-pyridinyl]methyl}oxy)-3-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)phenyl]ethanone

To a stirred solution of 1,1-dimethylethyl7-[5-acetyl-2-({[4-(ethyloxy)-2-pyridinyl]methyl}oxy)phenyl]-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate,(0.16 g) in DCM (2 ml) at OC was added TFA (0.247 g). This was stirredat room temperature for 16 h before concentrating and purifying bypreparative hplc. The title compound was isolated as the TFA salt, 0.058g

Mass Spec: [MH]+=417.2

HPLC: 6.81 min.

Similarly prepared was example 50:

Example Starting Material Amount Characterisation 50 1-[4-{[(4-{[2-(methyloxy)ethyl] oxy}-2- pyridinyl)methyl] oxy}-3-(2,3,4,5-tetrahydro-1H-3- benzazepin-7- yl)phenyl]ethanone

0.045 g HPLC Rt = 6.66 min Mass Spec: [MH]+ = 447

Example 377-{5-(methyloxy)-2-[(2-pyridinylmethy)oxy]phenyl}-2,3,4,5-tetrahydro-1H-3-benzazepine

(3-{[(1,1-dimethylethyl)oxy]carbonyl}-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)boronicacid (Preparation in WO2004056369) (0.125 g) was added to a stirredsolution of R19158/5/TC-1,2-({[2-bromo-4-(methyloxy)phenyl]oxy}methyl)pyridine, (0.085 g) in DME(2 ml) under an argon atmosphere at room temperature. After 1 min,aqueous sodium carbonate (2M, 3 mole equiv.) was added. After 2 min,tetrakis (0.016 g) was added and this was heated at 90C until completionof the reaction by tic. The crude product was partitioned between DCMand water. The aqueous was reextracted twice with DCM. The combinedorganics were dried over sodium sulphate, filtered and concentrated invacuo to yield a crude product. This was purified by columnchromatography (silica) using a gradient of ethyl acetate in cyclohexaneto yield the BOC-protected product. This was stirred in a solution ofHCl in ethyl acetate until reaction had gone to completion by tlc. Thisyielded the title compound as the hydrochloride salt, 0.03 g.

Mass Spec: [MH]+=361.1

HPLC: 6.06min.

Example 381-[4-[(2-pyridinylmethy)oxy]-3-(1,2,3,4-tetrahydro-7-isoquinolinyl)phenyl]ethanone

To a solution of1,1-dimethylethyl7-{5-acetyl-2-[(2-pyridinylmethyl)oxy]phenyl}-3,4-dihydro-2(1H)-isoquinolinecarboxylate(0.21 g) in dioxane was added a solution of HCl in dioxane (5 ml). Thereaction mixture was stirred at room temperature until it was complete(by TLC). It was concentrated in vacuo and the residue was purified bypreparative hplc to yield the title compound as the TFA salt, 0.055 g.

Mass Spec: [MH]+=359.1

HPLC: 6.59 min.

Example 467-{5-chloro-2-[(2-pyridinylmethyl)oxy]phenyl}-1,2,3,4-tetrahydroisoquinoline

To an ice cooled solution of, 1,1-dimethylethyl7-(5-chloro-2-{[(4-methyl-2-pyridinyl)methyl]oxy}phenyl)-3,4-dihydro-2(1H)-isoquinolinecarboxylate,(0.28 g) in DCM (1 ml) was added TFA (1 ml) and this was stirred at roomtemperature overnight. The reaction mixture was dissolved in water andbackwashed with ethyl acetate. The aqueous layer was neutralised withaqueous sodium bicarbonate and extracted with ethyl acetate. Theorganics were dried over sodium sulphate and concentrated in vacuo toyield the title compound, 0.12 g

LCMS (Method A): Rt=6.66 min, [MH]+=365

Example 487-(6-chloro-3-{[(4-methyl-2-pyridinyl)methyl]oxy}-2-pyridinyl)-2,3,4,5-tetrahydro-1H-3-benzazepine

To an ice cooled solution of1,1-dimethylethyl7-(6-chloro-3-{[(4-methyl-2-pyridinyl)methyl]oxy}-2-pyridinyl)-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylatein DCM (1 ml) was added dropwise TFA (1 ml) and the reaction mixturestirred at room temperature until the starting material had beenconsumed. The reaction mixture was concentrated in vacuo, dissolved inwater and backwashed with ethyl acetate. The aqueous layer wasneutralised with aqueous sodium bicarbonate then extracted with ethylacetate, dried over sodium sulphate and concentrated in vacuo to yieldthe title compound, 27 mg.

LCMS (Method A): Rt=6.33 min, [MH]+=380.1

Prepared similarly were the following examples:

Example Starting Material Amount Characterisation 49 7-(6-chloro-3-{[(4-methyl-2- pyridinyl)methyl] oxy}-2-pyridinyl)- 1,2,3,4-tetrahydroisoquinoline

0.027 g LCMS (Method B): Rt = 6.30 min, [MH]+ = 366.1 511-{3-(2,3-dihydro- 1H-isoindol-5-yl)- 4-[(2-pyridinyl- methyl)oxy]phenyl}ethanone

0.035 g HPLC Rt = 5.46 min Mass Spec: [MH]+ = 52 1-[4-[(2-pyridinylmethyl) oxy]-3-(1,2,3,4- tetrahydro-6- isoquinolinyl)phenyl]ethanone

0.063 g HPLC Rt = 5.57 min Mass Spec: [MH]+ = 359.1

Example 137-{2-(methyloxy)-6-[(2-pyrazinylmethyl)oxy]phenyl}-2,3,4,5-tetrahydro-1H-3-benzazepine,hydrochloride

To a solution of 1,1-dimethylethyl7-{2′-(methyloxy)-6′-[(2-pyrazinylmethyl)oxy]-4-biphenylyl}-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate(1.0 g) in DCM was bubbled dry HCl gas for 2 hours. The solvent wasremoved under reduced pressure and the residue was washed with diethylether. The precipitated solid was collected by filtration to give thetitle compound, 0.700 g

LCMS (Method C): Rt=1.49 min, [MH]+=362.2

Preparation of Polymorphic Forms of7-(2-(methyloxy)-6-{[(4-methyl-2-pyridinyl)methyl]oxy}phenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine

Form 1

The crystalline formof7-(2-(methyloxy)-6-{[(4-methyl-2-pyridinyl)methyl]oxy}phenyl)-2,3,4,5-tetrahydro-1H-3-benzazepinewas produced by a scale up 8 g of the method used to produce thecompound of Example 2A. It was characterised by one or more of themethods described below and was designated as Form 1.

Preparation of Form 2 Batch 1

40.0 mg of the Form 1 was combined with 1 mL of LC-grade water, mixedand temperature-cycled from 40° C. to 5° C. for 72 hours, thenequilibrated at 20° C. for 1 hour. The solids were isolated from thefiltrate by vacuum-filtration on a stainless steel analytical plate with10″-15″ vacuum at RT for ˜30 minutes.

Preparation of Form 2 Batch 2

237 mg of the input material was combined with 4 mL of HPLC-grade water.The slurry was seeded and thermocycled from 40° C. to 5° C. over 20hours. Raman assay of a filtered aliquot showed Form 2. Solids werefiltered by vacuum and dried in a vacuum oven at 20″ vacuum and 40° C.for 4 hours. Yield=197.6 mg. 150 mg of Form 1 was combined with 3 mL ofHPLC-grade water and stirred at RT (˜23° C.) for 18 hours. A smallaliquot was withdrawn, filtered, and assayed by Raman. The spectrum wasconsistent with Form 1. The slurry was seeded with Form 1 and stirred at40° C. for 4 hours. Raman assay of a filtered aliquot showed a mixtureof Form 1 and Form 2 with approximately 30% Form 2. The slurry wasthermocycled from 40° C. to 5° C. over 72 hours. Raman assay of afiltered aliquot showed only Form 2. The rest of the slurry wasfiltered. Raman assay of the isolated solid showed only Form 2. Thefiltered sample was dried at 30° C. with 20″ vacuum for 3.5 hours. Ramanassay showed only Form 1 consistent with batch 1. Dried yield=95 mg.

Characterisation methods

Powder X-ray diffractograms were acquired using either a PANalyticalX′Pert Pro diffractometer on Si zero-background wafers. Alldiffractograms were collected using a monochromatic Cu Ka (45 kV/40 mA)radiation and a step size of 0.02° 2θ. Peak positions were determinedusing Highscore software and the margin of error in peak positions isapproximately ±0.1° 2θ.

FIG. 1 shows the XRPD diffraction pattern for FORM 1. Table 1 shows themain degrees 2 theta peaks observed for FORM 1.

FIG. 4 shows the XRPD diffraction pattern for FORM 2. Table 2 shows themain degrees 2 theta peaks observed for FORM 2.

Table 3 shows the distinguishing features between the XRPD diffractionpattern for FORM 1 and FORM 2.

TABLE 1 XRPD peak positions for Form 1 Position/°2θ d-spacing/Å 11.7 7.512.7 7.0 13.7 6.5 14.6 6.1 16.0 5.5 17.8 5.0 18.9 4.7 19.4 4.6 20.2 4.421.2 4.2 22.6 3.9 23.0 3.9 23.7 3.8 24.0 3.7 24.4 3.6 25.1 3.5 25.5 3.526.1 3.4 26.9 3.3 27.5 3.2 28.1 3.2

TABLE 2 XRPD peak positions for Form 2 Position/°2θ d-spacing/Å 8.9 9.99.9 9.0 13.3 6.6 14.6 6.1 14.8 6.0 15.2 5.8 16.5 5.4 16.7 5.3 17.9 4.918.9 4.7 19.1 4.6 21.3 4.2 22.9 3.9 23.1 3.8 23.4 3.8 23.8 3.7 24.3 3.725.1 3.6 25.6 3.5 26.5 3.4 26.9 3.3 27.6 3.2

TABLE 3 XRPD peak d-spacing/Å Form 1 Form 2 11.7 8.9 12.7 9.9 13.7 13.316.0 15.2 16.7

FT-Raman Spectroscopy

Raman spectra were collected with a Nicolet NXR9650 (Thermo Electron)equipped with 1064 nm Nd:YVO4 excitation laser, InGaAs and liquid-N2cooled Ge detectors, and a MicroStage. All spectra were acquired at 4cm⁻¹ resolution, 64-128 scans, using Happ-Genzel apodization functionand 2-level zero-filling. Band positions were determined using Omnicsoftware and the margin of error in band positions isapproximately±1cm⁻¹.

FIG. 2 showns the FT-Raman Spectrum for FORM 1. Table 4 shows the mainpeaks observed for FORM 1.

FIG. 5 shows the FT-Ramen Spectrum for FORM 2. Table 5 shows the mainpeaks observed for FORM 2.

Table 6 shows the distinguishing features between the Raman Spectra forFORM 1 and FORM 2.

TABLE 4 Raman band positions for Form 1 Position/cm⁻¹ 202 226 250 312354 462 521 532 541 551 562 570 609 715 766 784 851 994 1018 1041 11031177 1189 1208 1236 1276 1295 1363 1415 1448 1464 1569 1610 2832 28652912 2945 2958 3059

TABLE 5 Raman band positions for Form 2 Position/cm⁻¹ 207 243 254 316337 388 442 463 537 554 572 614 715 736 748 777 856 964 1005 1022 10371107 1193 1210 1242 1289 1371 1422 1475 1571 1614 2787 2921 2934 29572973 2990 3014 3022 3043 3062 3084

TABLE 6 Raman band position/cm⁻¹ Form 1 Form 2 2945 2934 2832 1614 16101371 1363 1005 994 777 784

Differential Scanning Calorimetry (DSC)

Differential scanning calorimetry was conducted with a TAInstrumentsQ100 differential scanning calorimeter equipped with an autosampler anda refrigerated cooling system under 40 mL/min N₂ purge. DSC thermogramswere obtained at 15° C./min in crimped Al pans.

FIG. 3 shows the DSC thermogram of FORM 1.

FIG. 6 shows DSC thermogram of FORM 2.

1. A compound of formula (I):

wherein: X is CR₁ or N; Y is CH, C or N; R₁ is hydrogen, C₁₋₆alkoxy orC₁₋₆alkyl; R₂ is hydrogen, C₁₋₆alkoxy, halo, —C(O)C₁₋₆alkyl, CN,Halo-C₁₋₆alkyl or C(O)NR₄R₅; R₃ is hydrogen or C₁₋₆alkoxy; R₄ ishydrogen or C₁₋₆alkyl; R₅ is hydrogen or C₁₋₆alkyl; and m and n areintegers each independently selected from 1 and 2; or a salt thereof.